Analogs of discodermolide and dictyostatin-1, intermediates therefor and methods of synthesis thereof

ABSTRACT

A compound of the following structure: 
                         
wherein R 1  is H, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, or a halogen atom;
         R 2  is H, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ;   R a , R b  and R c  are independently an alkyl group or an aryl group;   R d  is an alkyl group, an aryl group, an alkoxylalkyl group, —R i SiR a R b R c  or a benzyl group, wherein R i  is an alkylene group;   R e  is an alkyl group, an allyl group, a benzyl group, an aryl group, an alkoxy group, or —NR g R h , wherein R g  and R h  are independently H, an alkyl group or an aryl group;   R 3  is (CH 2 ) n  where n is and integer in the range of 0 to 5, —CH 2 CH(CH 3 )—, —CH═CH—, —CH═C(CH 3 )—, or —C≡C—;   R 4  is (CH 2 ) p  where p is an integer in the range of 4 to 12, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 C(R s1 )═C(R s2 )C(R s3 )═C(R s4 )—, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 CH(R s1 ) CH(R s2 )C(R s3 )═C(R s4 )—, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 C(R s1 )═C(R s2 )CH(R s3 )CH(R s4 )—, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 CH(R s1 ) CH(R s2 )CH(R s3 )CH(R s4 )—, wherein y1 and y2 are 1 and y3, y4 and y5 are independently 0 or 1, R k1 , R k2 , R k3 , R k4  and R k5  are independently H, CH 3 , or OR 2a , and R s1 , R s2 , R s3 , and R s4  are independently H or CH 3 , wherein R 2a  is H, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ; and   R 5  is H or OR 2b , wherein R 2b  is H, an alkyl group, an aryl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ; provided that the compound is not dictyostatin 1.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/408,503, filed Sep. 6, 2002 and U.S. ProvisionalPatent Application Ser. No. 60/437,736 filed Jan. 2, 2003, thedisclosures of which are incorporated herein by reference.

GOVERNMENT INTEREST

This invention was made with government support under grant CA 78039awarded by the National Institutes of Health. The government has certainrights in this invention.

BACKGROUND OF THE INVENTION

The present invention relates to analogs of discodermolide anddictyostatin-1, intermediates for the synthesis of such analogs andmethods of synthesis of such intermediates and analogs.

References set forth herein may facilitate understanding of the presentinvention or the background of the present invention. Inclusion of areference herein, however, is not intended to and does not constitute anadmission that the reference is available as prior art with respect tothe present invention.

The discovery and development of new chemotherapeutic agents for thetreatment of cancer is currently of high importance. Some of the bestcurrently available chemotherapeutic agents are natural products ornatural product analogs. For example, Taxol (paclitaxel) is a naturalproduct that is currently being used to treat patients with breast andovarian cancer among others. A number of analogs of Taxol, includingTaxotere (docetaxel), are also powerful anticancer agents.

Recently, the natural product (+)-discodermolide and its analogs haveshown great promise as anticancer agents. Discodermolide has been shownto have a mechanism of action similar to Taxol but it is active againstTaxol-resistant cell lines and it is more water soluble than Taxol.Accordingly, it may have a different and/or broader spectrum of actionthan Taxol and be easier to formulate and administer. Like Taxol,discodermolide is difficult to synthesize. Some syntheses ofdiscodermolide are described in the following papers: Nerenberg, J. B.;Hung, D. T.; Somers, P. K.; Schreiber, S. L. Total synthesis of theimmunosuppressive agent (−)-discodermolide. J. Am. Chem. Soc. 1993, 115,12621–12622; Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K.Total Synthesis of (−)-Discodermolide. J. Am. Chem. Soc. 1995, 117,12011–12012; Marshall, J. A.; Johns, B. A. Total synthesis of(+)-discodermolide. J. Org. Chem. 1998, 63, 7885–7892; Paterson, I.;Florence, G. J.; Gerlach, K.; Scott, J. P. Total synthesis of theantimicrotubule agent (+)-discodermolide using boron-mediated aldolreactions of chiral ketones. Angew. Chem., Int. Ed. Eng. 2000, 39,377–380; Paterson, I.; Florence, G. J. Synthesis of (+)-discodermolideand analogues by control of asymmetric induction in aldol reactions ofgamma-chiral (Z)-enals. Tetrahedron Lett. 2000, 41, 6935–6939; Smith, A.B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y. P. et al.Evolution of a gram-scale synthesis of (+)-discodermolide. J. Am. Chem.Soc. 2000, 122, 8654–8664.

Analogs of discodermolide have also been made and tested for activity.For example, see the above references and Paterson, I.; Florence, G. J.;Gerlach, K.; Scott, J. P.; Sereinig, N. A practical synthesis of(+)-discodermolide and analogues: Fragment union by complex aldolreactions. J. Am. Chem. Soc. 2001, 123, 9535–9544; Martello, L. A.;LaMarche, M. J.; He, L.; Beauchamp, T. J.; Smith, A. B. et al. Therelationship between taxol and (+)-discodermolide: synthetic analogs andmodeling studies. Chemistry Biol. 2001, 8, 843–855; Harried, S. S.;Yang, G.; Strawn, M. A.; Myles, D. C. Total Synthesis of(−)-Discodermolide: An Application of a Chelation-Controlled AlkylationReaction. J. Org. Chem. 1997, 62, 6098–6099; Paterson, I.; Florence, G.J. Synthesis of (+)-discodermolide and analogues by control ofasymmetric induction in aldol reactions of gamma-chiral (Z)-enals.Tetrahedron Lett. 2000, 41, 6935–6939.

Unlike Taxol, discodermolide is not readily available in largequantities from natural sources. Accordingly, assuring a sufficientsupply of discodermolide is problematic. Simplified analogs that retainhigh anti-cancer activity but are easier to make are in urgent need.

Very recently, an unusual macrolactone natural product dictyostatin 1has been isolated from two different sponges and a partial structure hasbeen assigned as shown below. See Pettit, G. R.; Cichacz, Z. A.Isolation and structure of dictyostatin 1. In U.S. Pat. No. 5,430,053;1995; Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J.M. Isolation and structure of the cancer cell growth inhibitordictyostatin 1. J. Chem. Soc., Chem. Commun. 1994, 1111–1112. Theconfigurations at C16 and C19 have not yet been assigned in the naturalproduct and the absolute configuration is not known. Dictyostatin showsextremely high potencies against and array of cancer cell lines.

-   -   dictyostatin 1 absolute configuration unknown, configurations at        C16 and C19 unknown

Recently, dictyostatin has also been shown to stabilize microtubules,like discodermolide and Taxol. See Wright, A. E.; Cummins, J. L.;Pomponi, S. A.; Longley, R. E.; Isbrucker, R. A. Dictyostatin compoundsfor stabilization of microtubules. In PCT Int. Appl.; WO62239, 2001.Accordingly, dictyostatin 1 and its analogs show great promise as newanticancer agents. There is an urgent need for a synthetic route to makedictyostatin 1 and its analogs in order to fully assign the structure ofdictyostatin 1, to produce analogs to study the structure/activityrelationship and to identify and produce the best possible drugs in thisfamily.

The inventors of the present invention, as one aspect of the presentinvention, herein set forth a number of analogs of discodermolide, aswell as methods and intermediates for the synthesis thereof. Theinventors of the present invention, as another aspect of the presentinvention, herein set forth a family of both closed and open analogs ofdictyostatin 1 with methods and intermediates for the synthesis of thisfamily.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of thefollowing structure:

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom;

-   R² is H, an alkyl group, an aryl group, a benzyl group, a trityl    group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂)_(n) where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R⁴ is (CH₂)_(p) where p is an integer in the range of 4 to 12,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))    CH(R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))CH(R^(s3))CH(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH    (R^(s2))CH(R^(s3))CH(R^(s4))—, wherein y1 and y2 are 1 and y3, y4    and y5 are independently 0 or 1, R^(k1), R^(k2), R^(k3), R^(k4) and    R^(k5) are independently H, CH₃, or OR^(2a), and R^(s1), R^(s2),    R^(s3), and R^(s4) are independently H or CH₃, wherein R^(2a) is H,    an alkyl group, an aryl group, a benzyl group, a trityl group,    —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); and-   R⁵ is H or OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl    group, an aryl group, a benzyl group, a trityl group,    —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); provided that the    compound is not dictyostatin 1.

When groups including, but not limited to, —SiR^(a)R^(b)R^(c),CH₂OR^(d), and/or COR^(e) are set forth as a substituent for more thanone group in compounds of the claims and the specification of thepresent invention (for example, as a substituent of R², R^(2a), R^(s1),R^(s2), R^(s3), R^(s4) and R⁵ above), it is to be understood that thegroups of those substituents (R^(a), R^(b), R^(c), R^(d), and R^(e) inthis example), are independently, the same of different within eachgroup and among the groups.

In one embodiment, the compound has the following stereostructure, orits enantiomer:

wherein R¹ is alkenyl; R² is H; R³ is —CH₂CH(CH₃) or —CH═C(CH₃); and R⁴is—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))— wherein y1–y4 are 1, y5 is 0, R^(k1) andR^(k3) are OH, R^(k2) is H, R^(k4) is CH₃, R^(s1), R^(s2), R^(s3) andR^(s4) are H, and R⁵ is OH.

In one embodiment, R¹ is —CH═CH₂ and R⁴ is

In another aspect, the present invention provides a compound of thefollowing structure:

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom;

-   R² and R^(2d) are independently H, an alkyl group, an aryl group, a    benzyl group, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or    COR^(e);-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂)_(n) where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R⁴ is (CH₂)_(p) where p is an integer in the range of 4 to 12,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C    (R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH    (R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C    (R^(s2))CH(R^(s3))CH(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH    (R^(s2))CH(R^(s3))CH(R^(s4))—, wherein y1 and y2 are 1 and y3, y4    and y5 are independently 0 or 1, R^(k1), R^(k2), R^(k3), R^(k4) and    R^(k5) are independently H, —CH₃, or OR^(2a), and R^(s1), R^(s2),    R^(s3), and R^(s4) are independently H or CH₃, wherein R^(2a) is H,    an alkyl group, an aryl group, a benzyl group, a trityl group,    —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); and-   R⁵ is H or OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e); and-   R¹⁰ is H or alkyl.

In one embodiment, the compound has the following stereostructure, orits enantiomer

wherein R¹ is alkenyl; R² is H; R^(2d) is H, OC(O)CH₃ orOC(O)NR^(g)R^(h) wherein R^(g) and R^(h) are independently H, an alkylgroup or an aryl group; R³ is CH₂CH(CH₃) or CH═C(CH₃); and R⁴ is—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))— wherein y1–y4 are 1, y5 is 0, R^(k1) andR^(k3) are OH, R^(k2) is H, R^(k4) is CH₃, R^(s1), R^(s2), R^(s3) andR^(s4) are H, R⁵ is OH; and R¹⁰ is H or alkyl.

In another embodiment, R¹ is —CH═CH₂, and R^(2d) is H, OC(O)CH₃ orOC(O)NH₂.

In a further aspect, the present invention provides a compound of thefollowing structure:

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom;

-   R² and R^(2d) are independently H, an alkyl group, an aryl group, a    benzyl group, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or    COR^(e);-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂)_(n) where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R⁵ is H or OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e);-   R^(11a) and R^(11b) are independently H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), COR^(e), or R^(11a) and R^(11b) together form a portion    of six-membered acetal ring incorporating CR^(t)R^(u);-   R^(t) and R^(u) are independently H, an alkyl group, an aryl group    or an alkoxyarly group; and-   R¹² is a halogen atom, CH₂OR^(2c), CHO, CO₂R¹⁰, CH═CHCH₂OR^(2c),    CH═CHCHO, wherein-   R^(2c) is H, an alkyl group, an aryl group, a benzyl group, a trityl    group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e), and R¹⁰ is H or    alkyl.

In one embodiment, the compound has the following stereostructure, orits enantiomer

wherein R¹ is alkenyl; R^(2d) is H, OC(O)CH₃ or OC(O)NR^(g)R^(h) whereinR^(g) and R^(h) are independently H, an alkyl group or an aryl group; R³is CH₂CH(CH₃) or CH═C(CH₃); R^(11a) and R^(11b) are H or together form aportion of a six-membered acetal ring containing C(H)(p-C₆H₄OCH₃) orC(CH₃)₂; R¹² is a halogen atom, CH₂OR^(2c), CHO, CO₂R¹⁰,CH═CHCH₂OR^(2c), CH═CHCHO, wherein R^(2c) is H, an alkyl group, an arylgroup, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), orCOR^(e), and R¹⁰ is H or alkyl.

In another embodiment, R¹ is —CH═CH₂, R^(2d) is H, —OC(O)CH₃ or—OC(O)NH₂, and R¹² is —CH₂OH, —CHO or —CO₂R¹⁰.

In another aspect, the present invention provides a compound having thefollowing structure:

wherein R² is H, an alkyl group, an aryl group, a benzyl group, a tritylgroup, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);

-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂)_(n) where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R⁵ is H or OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e);-   R^(11a) and R^(11b) are independently H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), COR^(e), or R^(11a) and R^(11b) together form a portion    of six-membered acetal ring containing CR^(t)R^(u);-   R^(t) and R^(u) are independently H, an alkyl group, an aryl group    or an alkoxy aryl group;-   R¹² is a halogen atom, CH₂OR^(2c), CHO, CO₂R¹⁰, CH═CHCH₂OR^(2c) or    CH═CHCHO, CH═CHCO₂R¹⁰, wherein R^(2c) is H, an alkyl group, a benzyl    group, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e),    and R¹⁰ is H or alkyl; and-   R^(14a) and R^(14b) are independently H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), COR^(e), or R^(14a) and R^(14b) together form a    six-membered ring containing CR^(v)R^(w), wherein R^(v) and R^(w)    are independently H, an alkyl group, an aryl group or an alkoxyaryl    group.

In one embodiment, the compound has the following stereostructure, orits enantiomer

R² is H; R^(2d) is H, OC(O)CH₃ or OC(O)NR^(g)R^(h) wherein R^(g) andR^(h) are independently H, an alkyl group or an aryl group; R³ isCH₂CH(CH₃) or CH═C(CH₃); R^(11a) and R^(11b) are H or together form aportion of a six-membered acetal ring containing C(H)(p-C₆H₄OCH₃) orC(CH₃)₂; R¹² is a halogen atom, CH₂OR^(2c), CHO, CO₂R¹⁰,CH═CHCH₂OR^(2c), CH═CHCHO or CH═CHCO₂R¹⁰, wherein R^(2c) is H, an alkylgroup, an aryl group, a benzyl group, a trityl group,—SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e), and R¹⁰ is H or alkyl; andR^(14a) and R^(14b) are H or together form a portion of a six-memberedacetal ring containing C(H)(p-C₆H₄OCH₃) or C(CH₃)₂.

In another aspect, the present invention provides a compound having thefollowing formula

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom;

-   R² is H, an alkyl group, an aryl group, a benzyl group, a trityl    group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂)_(n) where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R^(11a) and R^(11b) are independently H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), COR^(e), or R^(11a) and R^(11b) together form a portion    of six-membered acetal ring containing CR^(t)R^(u);-   R^(t) and R^(u) are independently H, an alkyl group, an aryl group    or an alkoxyarly group;-   R¹² is a halogen atom, CH₂OR^(2c), CHO, CO₂R¹⁰, CH═CHCH₂OR^(2c),    CH═CHCHO or CH═CHCO₂R¹⁰, wherein R^(2c) is H, an alkyl group, an    aryl group; a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e), and R¹⁰ is H or alkyl; and-   R^(14a) and R^(14b) are independently H, an alkyl group, and aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), COR^(e), or R^(14a) and R^(14b) together form a    six-membered ring containing CR^(v)R^(w), wherein R^(v) and R^(w)    are independently H, an alkyl group, an aryl group or an alkoxyaryl    group.

In one embodiment, the compound has the following stereostructure, orits enantiomer

wherein R³ is CH₂CH(CH₃) or CH═C(CH₃); R^(11a) and R^(11b) are H ortogether form a portion of a six-membered acetal ring containingC(H)(p-C₆H₄OCH₃) or C(CH₃)₂; R¹² is a halogen atom, CH₂OR^(2c), CHO,CO₂R¹⁰, CH═CHCH₂OR^(2c), CH═CHCHO or CH═CHCO₂R¹⁰, wherein

-   R^(2c) is H, an alkyl group, an aryl group, a benzyl group, a trityl    group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e), and R¹⁰ is H or    alkyl; and R^(14a) and R^(14b) are H or together form a portion of a    six-membered acetal ring containing C(H)(p-C₆H₄OCH₃) or C(CH₃)₂.

In a further aspect, the present invention provides a compound havingthe following formula

wherein R² is H, an alkyl group, an aryl group, a benzyl group, a tritylgroup, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);

-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R^(11a) and R^(11b) are independently H, an alkyl group, and aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), COR^(e), or R^(11a) and R^(11b) together form a portion    of six-membered acetal ring containing CR^(t)R^(u);-   R^(t) and R^(u) are independently H, an alkyl group, an aryl group    or an alkoxyarly group;-   R¹² is a halogen atom, CH₂OR^(2c), CHO, CO₂R¹⁰, CH═CHCH₂OR^(2c),    CH═CHCHO or CH═CHCO₂R¹⁰, wherein R^(2c) is H, an alkyl group, an    aryl group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e), and R¹⁰ is H or alkyl;-   R¹⁶ is H or alkyl; and-   R¹⁷ is CH₂OR^(2f), CHO, CO₂R¹⁰, wherein R^(2f) is H, an alkyl group,    a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or    COR^(e).

In one embodiment, the compound has the following stereostructure, orits enantiomer

wherein R² is H, an alkyl group, a benzyl group, a trityl group,—SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); R^(11a) and R^(11b) are H ortogether form a portion of a six-membered acetal ring containingC(H)(p-C₆H₄OCH₃) or C(CH₃)₂; and R¹⁶ is H or alkyl.

In still a further aspect, the present invention provides a compoundhaving the following formula

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom;

-   R², R^(2d) and R^(2e) are independently H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e);-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂)_(n) where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R⁵ is H or OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e); q is an integer in the range of 2 to 5;-   R¹⁸ is H, and R¹⁹ is hydroxy, alkoxy or —SR^(z), wherein R^(z) is an    alkyl group or an aryl group, or R¹⁸ and R¹⁹ taken together are ═O.

In one embodiment, the compound has the following stereostructure, orits enantiomer

In one embodiment of the compound, R¹ is a CH═CH₂ and R³ is (Z)—CH═CH—,or —CH₂CH₂—.

In a further aspect, the present invention provides a compound havingthe following structure

-   R^(11a) and R^(11b) are independently H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), COR^(e), or R^(11a) and R^(11b) together form a portion    of six-membered acetal ring containing CR^(t)R^(u);-   R^(t) and R^(u) are independently H, an alkyl group, an aryl group    or an alkoxyarly group;-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R²⁰ is CH₂OR^(2g), CHO, CO₂R¹⁰; wherein R^(2g) is H, an alkyl group,    an aryl group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e), and wherein R¹⁰ is H or alkyl; and-   R²¹ is a halogen atom, CH₂OR^(2c), CHO, CO₂R^(10a), CH═CHCH₂OR^(2c),    CH═CHCHO or CH═CHCO₂R¹⁰, wherein R^(2c) is H, an alkyl group, an    aryl group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e), and wherein R^(10a) is H or alkyl.

In one embodiment, the compound has the following stereostructure, orits enantiomer

wherein R^(11a) and R^(11b) are independently H, an alkyl group, andaryl group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),CH₂OR^(d), COR^(e), or R^(11a) and R^(11b) together form a portion ofsix-membered acetal ring incorporating CR^(t)R^(u);

-   R^(t) and R^(u) are independently H, an alkyl, an aryl group or an    alkoxyarly group;-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R²⁰ is CH₂OR^(2g), CHO, CO₂R¹⁰; wherein R^(2g) is H, an alkyl group,    a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or    COR^(e), and wherein R¹⁰ is H or alkyl; and-   R²¹ is a halogen atom, CH₂OR^(2c), CHO, CO₂R^(10a), CH═CHCH₂OR^(2c),    CH═CHCHO, CH═CHCO₂R¹⁰ wherein R^(2c) is H, an alkyl group, a benzyl    group, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e),    and wherein R^(10a) is H or alkyl.

In one embodiment, R^(11a) and R^(11b) are H or together form a portionof a six-membered acetal ring containing C(H)(p-C₆H₄OCH₃) or C(CH₃)₂;R²¹ is a halogen atom, CH₂OR^(2c), CHO, CO₂R¹⁰, CH═CHCH₂OR^(2c),CH═CHCHO, wherein R^(2c) is H, an alkyl group, an aryl group, a benzylgroup, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e), andR¹⁰ is H or alkyl.

In another embodiment, R¹ is CH═CH₂, and R²¹ is CH₂OH, CHO or CO₂R¹⁰.

In still another aspect, the present invention provides a compoundhaving the following formula

wherein R¹³ is H or an alkyl group, R¹⁴ is H, an aryl group, analkoxyaryl group or an alkyl group, and R²² is a halogen atom or—P(Ar)₃X, wherein X is a counteranion selected from the groups halide,tetrafluoroborate, hexafluorophosphate and sulfonate, provided that whenR¹³ and R¹⁴ are methyl groups, X is not I. In one embodiment, when R¹³and R¹⁴ are alkyl groups, X is not halogen.

In another embodiment, the compound has the following stereostructure,or its enantiomer

wherein R¹³ is H or an alkyl group, and R¹⁴ is H, an aryl group, analkoxyaryl group, or an alkyl group, an aryl group or an alkoxyarlygroup, R²² is a halogen atom or —P(Ar)₃X, wherein X is a counteranionselected from the groups halide, tetrafluoroborate, hexafluorophosphateand sulfonate, provided that when R¹³ and R¹⁴ are methyl groups, X isnot I.

In one embodiment, R¹³ is H, R¹⁴ is aryl, and R²² is P(C₆H₅)₃X. Inanother embodiment, R¹⁴ is C₆H₄-p-OCH₃.

In still a further aspect, the present invention provides a process forconversion of a first compound with the formula

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom;

-   R² is H, an alkyl group, an aryl group, a benzyl group, a trityl    group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);-   R^(2d) is H-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂)_(n) where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R⁴ is (CH₂)_(p) where p is an integer in the range of 4 to 12,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C    (R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH    (R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C    (R^(s2))CH(R^(s3))CH(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH    (R^(s2))CH(R^(s3))CH(R^(s4))—, wherein y1 and y2 are 1 and y3, y4    and y5 are independently 0 or 1, R^(k1), R^(k2), R^(k3), R^(k4) and    R^(k5) are independently H, CH₃, or OR^(2a), and R^(s1), R^(s2),    R^(s3), and R^(s4) are independently H or CH₃, wherein R^(2a) is H,    an alkyl group, an aryl group, a benzyl group, a trityl group,    —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); and-   R⁵ is H or OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e); and-   R¹⁰ is H;    to a second compound with the formula

comprising the step of reacting the first compound under conditionssuitable to effect macrolactonization.

In one embodiment, the process is for conversion of a compound with thefollowing stereostructure or its enantiomer

wherein R¹ is H, an alkyl group, an alkenyl group, an alkynyl group, ora halogen atom;

-   R² is H, an alkyl group, an aryl group, a benzyl group, a trityl    group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);-   R^(2d) is H-   R^(a), R^(b) and R^(c) are independently an alkyl group or an aryl    group;-   R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,    —R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an    alkylene group;-   R^(e) is an alkyl group, an allyl group, a benzyl group, an aryl    group, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) are    independently H, an alkyl group or an aryl group;-   R³ is (CH₂), where n is and integer in the range of 0 to 5,    —CH₂CH(CH₃)—, —CH═CH—, —CH═C(CH₃)—, or —C≡C—;-   R⁴ is (CH₂)_(p) where p is an integer in the range of 4 to 12,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C    (R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH    (R^(s2))C(R^(s3))═C(R^(s4))—,    —(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C    (R^(s2))CH(R^(s3))CH(R^(s4))—,    —(CHR^(k))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH    (R^(s2))CH(R^(s3))CH(R^(s4))—, wherein y1 and y2 are 1 and y3, y4    and y5 are independently 0 or 1, R^(k1), R^(k2), R^(k3), R^(k4) and    R^(k5) are independently H, —CH₃, or OR^(2a), and R^(s1), R^(s2),    R^(s3), and R^(s4) are independently H or CH₃, wherein R^(2a) is H,    an alkyl group, an aryl group, a benzyl group, a trityl group,    —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);-   R⁵ is H or OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl    group, a benzyl group, a trityl group, —SiR^(a)R^(b)R^(c),    CH₂OR^(d), or COR^(e); and-   R¹⁰ is H    to a second compound with the formula

In one embodiment of the process, R¹ is alkenyl; R³ is CH₂CH(CH₃) orCH═C(CH₃); and R⁴ is—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))— wherein y1–y4 are 1, y5 is 0, R^(k1) andR^(k3) are R^(2a), R^(k2) is H, R^(k4) is CH₃, R^(s1)–R^(s4) are H, andR⁵ is OR^(2b).

In another embodiment of the process, R¹ is CH═CH₂ and R⁴ is

In one embodiment of the process, the first compound is converted byreacting the first compound with 2,4,6-trichlorobenzoylchloride.

The above general structures for the compounds of the present inventioninclude all stereoisomers thereof (other than the natural compounddictyostatin 1). Moreover, the structures of the compounds of thepresent invention include the compounds in racemic form,enantiomerically enriched form or enantiomerically pure form.

The terms “alkyl”, “aryl” and other groups refer generally to bothunsubstituted and substituted groups unless specified to the contrary.In that regard, the groups set forth above can be substituted with awide variety of substituents to synthesize analogs retaining biologicalactivity. Unless otherwise specified, alkyl groups are hydrocarbongroups and are preferably C₁–C₁₅ (that is, having 1 to 15 carbon atoms)alkyl groups, and more preferably C₁–C₁₀ alkyl groups, and can bebranched or unbranched, acyclic or cyclic. The above definition of analkyl group and other definitions apply also when the group is asubstituent on another group (for example, an alkyl group as asubstituent of an alkylamino group or a dialkylamino group). The term“aryl” refers to phenyl or naphthyl. As used herein, the terms “halogen”or “halo” refer to fluoro, chloro, bromo and iodo.

The term “alkoxy” refers to —OR, wherein R is an alkyl group. The term“alkenyl” refers to a straight or branched chain hydrocarbon group withat least one double bond, preferably with 2–15 carbon atoms, and morepreferably with 2–10 carbon atoms (for example, —CH═CHR or —CH₂CH═CHR;wherein R can be a group including, but not limited to, an alkyl group,an alkoxyalkyl group, an amino alkyl group, an aryl group, or a benzylgroup). The term “alkynyl” refers to a straight or branched chainhydrocarbon group with at least one triple bond, preferably with 2–15carbon atoms, and more preferably with 2–10 carbon atoms (for example,—C≡CR or —CH₂—C≡CR; wherein R can be a group including, but not limitedto, an alkyl group, an alkoxyalkyl group, an amino alkyl group, an arylgroup, or a benzyl group). The terms “alkylene,” “alkenylene” and“alkynylene” refer to bivalent forms of alkyl, alkenyl and alkynylgroups, respectively.

The term “trityl” refers to a triphenyl methyl group or —C(Ph)₃.

Certain groups such as amino and hydroxy groups may include protectivegroups as known in the art. Preferred protective groups for amino groupsinclude tert-butyloxycarbonyl, formyl, acetyl, benzyl,p-methoxybenzyloxycarbonyl, trityl. Other suitable protecting groups asknown to those skilled in the art are disclosed in Greene, T., Wuts, P.G. M., Protective Groups in Organic Synthesis, Wiley (1991), thedisclosure of which is incorporated herein by reference.

Other aspects of the present invention include the synthesis of thecompounds of the present invention as well as the biological assaying ofsuch compound and the biological activity of such compounds against, forexample, cancer (such as breast, prostate cancer and ovarial cancer).For example, in another aspect, the present invention provides a methodof treating a patient for cancer, including the step of administering apharmaceutically effective amount of a biologically active compound ofthe present invention or a pharmaceutically acceptable salt thereof.

The present invention, along with the attributes and attendantadvantages thereof, will best be appreciated and understood in view ofthe following detailed description taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates one embodiment of the syntheses of a representativeisomeric aldehyde for incorporation of the left part of theconfiguration of (+)-discodermolide.

FIG. 2 illustrates one embodiment of the syntheses of anotherrepresentative isomeric aldehyde for incorporation of the left part ofthe configuration of (+)-discodermolide.

FIG. 2 illustrates one embodiment of the syntheses of an intermediatefor the center part of the configuration of (+)-discodermolide.

FIG. 4 illustrates one embodiment of the construction of the rightfragment or part of the molecule.

FIG. 5 illustrates an embodiment of the synthesis of severaldiscodermolide analogs of the present invention.

FIGS. 6A through D illustrate the tubulin polymerization-inducingproperties of discodermolide (Figure A), as well as discodermolideanalog compounds 40 (Figure B), 41 (Figure C) and 42 (Figure D) of thepresent invention in comparison to 10 μM paclitaxel (PTX).

FIG. 7 illustrates a retrosynthetic analysis of a dictyostatin analog ofthe present invention.

FIG. 8 illustrates an embodiment of the coupling of three fragments of adictyostatin analog of the present invention.

FIG. 9 illustrates the structures of several acyclic compounds of thepresent invention that were tested for biological activity.

FIG. 10 illustrates an embodiment of the synthesis of a lower fragmentof a dictyostatin analog of the present invention.

FIG. 11 illustrates an embodiment of the synthesis of a macrolactone ofthe present invention.

FIG. 12 illustrates a second representative general scheme for synthesisof stereoisomers and analogs of dictyostatin.

FIG. 13 illustrates a summary of an embodiment of the synthesis of thebottom fragment of dictyostatin analogs of the present invention.

FIG. 14 illustrates an embodiment of the coupling of the bottom fragmentof FIG. 13 with the center fragment of the dictyostatin analogs of thepresent invention.

FIG. 15 illustrates an embodiment of the introduction of the C16stereocenter and introduction of the top fragment of the dictyostatinanalog of the present invention.

FIG. 16 illustrates an embodiment of the completion of the synthesis ofthe dictyostatin analog of the present invention.

FIG. 17 illustrates embodiments of representative methods to makeanalogs of the terminal diene fragment of the dictyostatin analog of thepresent invention.

FIG. 18 illustrates a summary of an embodiment of the synthesis of thebottom fragment of the dictyostatin analog of the present invention.

FIG. 19 illustrates an embodiment of the synthesis of two fragments withanti/anti configurations as assigned to dictyostatin 1 at C13–C15.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of Simplified Analogs of Discodermolide: The inventors of thepresent invention hypothesized that active analogs of discodermolidewould result after removal of the C14 and C16 methyl groups and the C7hydroxy group. These deletions greatly simplify the synthesis byallowing the two cis-disubstituted alkenes of analogs 1 and 2 to be madeby Wittig-type reactions. A family of simple analogs 1 were shown tohave moderate activity. However, by incorporating a lactone in place ofthe simple ester side chains of 1, the inventors of the presentinvention have discovered anti-cancer agents of increased activity thatare still significantly simpler to make than discodermolide.

The syntheses of two representative isomeric aldehydes 9 a and 9 b forincorporation of the left part of these molecules are shown in FIGS. 1and 2. he synthesis of the left display bearing the configuration of(+)-discodermolide started with the commercially available methacrolein3 (FIG. 1). Reaction of 3 with the boron enolate of Evans oxazolidinone4 gave the corresponding alcohol, which was silylated to give compound 5in 90% yield. Lactonization followed by the introduction of allyl groupwas performed by the previously reported method to give 6 in good yield.See Day, B. W.; Kangani, C. O.; Avor, K. S. Convenient syntheses of(2R,3S,4R)-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-5-oxopentanoicacid methoxymethyl-amide from methacrolein. Preparation of C1–C7 andC17–C24 fragments of (+)-discodermolide. Tetrahedron Asymmetry 2002, 13,1161–1165. Lactone opening, oxidation and allylation gave 7. Conversionto the methyl acetal was accomplished by DIBAL (diisobutylaluminumhydride) reduction to the corresponding lactol followed by treatmentwith camphorsulfonic acid (CSA) in methanol to give a desilylatedintermediate, which was protected with methoxymethyl chloride (MOMCl) togive a mixture of anomers 8 (β:α=1:1). These were separable by silicagel flash chromatography. The final left fragment 9 a was obtained byhydroboration of the α-anomer 8 with BH₃-DMS (borane-dimethysulfide)followed by oxidation with SO₃-pyridine.

The synthesis of the C4-epi lactone left display 9 b started from1,4-butanediol (FIG. 2). Monoprotection with PMB bromide (PMB isp-methoxybenzyl) was performed with NaH in DMF. After oxidation,reaction of the crude aldehyde 10 with the boron enolate of Evansoxazolidinone 4 gave the corresponding syn-alcohol, which was silylatedto give compound 11 in 90% yield. Lithium borohydride reduction followedby oxidation gave the aldehyde 12. A second syn-aldol addition wasperformed with same Evans oxazolidinone 4 to give the correspondingalcohol, which was protected with MOM chloride to give compound 13.Desilylation of 13 with HF gave the cyclized product 14 in high yield.Conversion to the methyl acetal was easily accomplished by DIBALreduction to the corresponding lactol followed by treatment with PPTS(pyridinium p-toluene sulfonate) in methanol to give 15 as a 2.5:1 (α:β)mixture of anomers from which the major anomer (α) was isolated bysilica gel flash chromatography. The final left fragment 9 b wasobtained by hydrogenolysis of the PMB protecting group followed byDess-Martin oxidation.

These synthetic routes are flexible and substantially any stereoisomerof the lactone 9 can be made with the appropriate chiral auxiliary andreaction conditions.

Center intermediate 21 was prepared as shown in FIG. 3. Oxazolidinone 18was prepared from (S)-3-hydroxy-2-methylpropionic methyl ester 16 by theknown procedure for the preparation of ent-18. See Clark, D. L.;Heathcock, C. H. Studies on the alkylation of chiral enolates:application toward the total synthesis of discodermolide. J. Org. Chem.1993, 58 5878–5879. Reduction of 18 with lithium borohydride gave thediol, which was protected by anisaldehyde dimethyl acetal 19 to give theacetal 20. Deprotection of the primary TBS group with tetrabutylammoniumfluoride (TBAF), iodination, and treatment with triphenylphosphineafforded the phosphonium salt 21 in 72% yield. Phosphonium salts 22 and23 were also used for Wittig olefination, but the results wereunsatisfactory. Smith also encountered difficulties with related Wittigreagents in discodermolide synthesis. See: Smith, A. B.; Beauchamp, T.J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y. P. et al. Evolution of agram-scale synthesis of (+)-discodermolide. J. Am. Chem. Soc. 2000, 122,8654–8664. These difficulties may result, at least in part, from thehygroscopic nature of the phosphonium salts. In contrast, compound 21 isa white, non-hygroscopic solid and its Wittig reactions were reliableeven though no special care was taken with its storage (for example,salt 21 was useful for reactions even after it was stored at roomtemperature for several months).

As shown in FIG. 4, the construction of the right fragment 34 featuredaldol reactions. Syn-Aldol reaction of aldehyde 24 with 4 provided 25,which was reduced to a diol and protected with anisaldehyde dimethylacetal 19 to give 26. Selective opening of the benzylidine ring of 26with DIBAL gave a primary alcohol, which was oxidized to aldehyde 27.The subsequent anti-aldol condensation using Heathcock's aldol reactionwith dimethylphenyl propionate 28 furnished compound 29 as the majorproduct in 73% yield. See Heathcock, C. H.; Pirrung, M. C.; Montgomery,S. H.; Lampe, J. Acyclic stereoselection-13; Aryl esters: reagents forthreo-aldolization. Tetrahedron 1981, 37, 4087–4095. The relativeconfiguration of intermediate 29 was confirmed by ¹³C and ¹H NMRanalyses of the corresponding acetonide 34. Silylation of the newlyformed hydroxyl group of 29, reduction of the aryl ester with DIBAL andDess-Martin oxidation of the resultant primary alcohol afforded aldehyde30. The Z-diene moiety was introduced by a two-step procedure developedby Paterson and coworkers using a Nozaki-Hiyama reaction. See Paterson,I.; Schlapbach, A. Studies towards the total synthesis of themarine-derived immunosuppresant discodermolide: stereoselectivesynthesis of a C9–C24 subunit. Synlett. 1995, 498–500. Addition of thealdehyde 30 and allyl bromide 31 to a suspension of CrCl₂ in THFproduced an intermediate β-hydroxy silane (not shown), which upontreatment with NaH underwent syn elimination to generate the requiredZ-diene 32. Selective deprotection of the primary TBS group, iodination,and then treatment with triphenylphosphine gave the phosphonium salt 33in good yield.

The first Wittig reaction of 9 a with 21 provided 35 (see FIG. 5). DIBALreductive cleavage of the acetal followed by Dess-Martin oxidation gavealdehyde 37. Likewise, aldehyde 38 was made from 9 b via 36. The secondWittig olefination was accomplished with 38 as an example andphosphonium salt 33 (FIG. 5). Tetrabutylammonium fluoride deprotectionfollowed by carbamoylation using Koçovsky's method (See Koçovsky, P.Carbamates: a method of synthesis and some synthetic applications.Tetrahedron Lett. 1986, 27 5521–5524) afforded the C19carbamate-containing compound 39. The lactone was built from the methylacetal in the left fragment by using aqueous 60% acetic acid in THFfollowed by Dess-Martin oxidation. Deprotected analog 40 containing afree C3 hydroxy group on the lactone was obtained by the removal of MOMgroup with 4N HCl followed by removal of the PMB protecting groups withDDQ oxidation. Two additional example compounds, 41 and 42, wereprepared from the intermediate 39 by using appropriate conditions. Allthree of these analogs exhibited significant activity, as shown in FIGS.6A–D and Table 1. Surprisingly, the C3-MOM-protected analogs 41 and 42showed better microtubule hypernucleation activities than the analog 40with a free C3-hydroxy group. As can be seen in FIG. 6A, discodermolideis superior to paclitaxel (taxol) in that it causes equivalentmicrotubule assembly at both lower concentrations and temperatures (theincrease in absorbance caused by discodermolide occurs at a time pointearlier than that caused by paclitaxel). Additionally, the polymerinduced to form by discodermolide is more resistant to cold-induceddisassembly than is the paclitaxel-induced polymer. Both analogs 41(FIG. 6C) and 42 (FIG. 6D) showed these more rapid polymer-inducing andcold-resistant properties, albeit at somewhat lower potencies (forexample, higher concentrations of the analogs were necessary for theseeffects to be detected) than discodermolide. MOM ether lactone 41 wasthe most potent among these analogs.

Table 1 shows microtubule stabilizing, antiproliferative, andpaclitaxel-displacing properties of 40–42. Again, the lactone, MOM ether41 was more potent than the lactol 42 or free hydroxy 40 relatives. Thecellular activity of 41 was good, showing a submicromolar 50% growthinhibitory (GI₅₀) concentration. This compound also showed considerableaffinity for the paclitaxel binding site on tubulin. A 2-fold molarexcess of 41 displaced [³H]paclitaxel from microtubules better thanpaclitaxel and at almost the same potency as discodermolide.

TABLE 1 Microtubule stabilizing, antiproliferative andpaclitaxel-displacing properties of compounds 40–42 in comparison to(+)-discodermolide (1) and paclitaxel. MT GI₅₀ (μM)^(b) Displacement ofstabilizing MDA-MB231 2008 [³H]paclitaxel Compound activity (%)^(a)(breast) PC3 (prostate) (ovarian) (%)^(c) discodermolide >100 0.016 ±0.003 0.067 ± 0.004 0.072 ± 0.005 64 ± 2 paclitaxel 100 0.0024 ± 0.00160.015 ± 0.002 0.0092 ± 0.0016 37 ± 1 40 11 2.1 ± 1.8 7.5 ± 2.0 5.2 ± 1.021 ± 1 41 27 0.87 ± 0.21 1.8 ± 0.9 0.65 ± 0.25 57 ± 2 42 11 3.4 ± 0.8 15± 3  4.7 ± 0.6 19 ± 2 ^(a)Percent tubulin assembly induced by test agentat 10 μM vs. that caused by 10 μM paclitaxel (100%); singledeterminations at 30° C. ^(b)Concentration at which test agent caused50% inhibition of cell growth; means (N = 4 over 10 concentrations) ± SDafter 72 h of continuous exposure to the agent. ^(c)Percent displacementby 4 μM test agent of 2 μM [³H]paclitaxel bound to microtubules formedfrom 2 μM tubulin and 20 μM dideoxyGTP.

Macrocycle 43 is a representative example of a dictyostatin analog withan alkyl chain bridging the lactone carbonyl group and the C10/C11alkene and with two Z-double bonds in the macrocycle. It can also beconsidered as a macrocyclic analog of discodermolide. This can besynthesized convergently from three components—33, 21 and 44—viasequential Wittig couplings and a macrocyclization (FIG. 7). This designallows the synthesis of substantially any stereoisomer by employing thedesired isomer of the relevant precursor—21 or 33.

Fragment 45 was synthesized from 1,10-decanediol (not shown) by mono-TBSprotection (NaH/TBSCl, 42%) followed by Dess-Martin oxidation (80%).Fragment 21 was prepared as shown in FIG. 3. Fragment 33 was prepared asshown in FIG. 4.

The coupling of the three fragments is summarized in FIG. 8. Generationof the ylide from phosphonium salt 21 and NaHDMS followed by addition ofaldehyde 44 gave the Wittig product in good yield (75%) provided thatthe reaction was conducted at high concentration (1M in 21). Theformation of the Z-alkene was confirmed by the 10 Hz coupling constantbetween the vinyl protons. Selective opening of the PMB acetal wasaccomplished by addition of 3 equiv of DIBAL to give a primary alcohol.This was oxidized to an aldehyde under Dess-Martin conditions. Wittigconditions similar to those above were then deployed to prepare 45 fromthis aldehyde and phosphonium salt 33.

Selective deprotection of 45 was achieved using HF-pyridine and theresulting primary alcohol was oxidized to acid 46. The other TBS groupwas then removed with TBAF. Using the Yamaguchi protocol, themacrolactone ring was then constructed. PMB deprotection using DDQprovided target product 43, whose protons and carbons were assigned byCOSY and HMQC NMR experiments. The location of the macrolactone ring wasconfirmed by HMBC NMR experiments.

Acyclic compounds 47, 48 and 49 were readily made from appropriatesynthetic intermediates (45 or 46) in reasonable yields (FIG. 9).

These analogs were tested for antiproliferative activity in vitroagainst two human cancer cell lines (Table 2). Macrolactone 43 andnon-cyclized alcohol 47 and ester 48 exhibited similar 50% growthinhibitory concentrations, in the 15–30 μM range. Carboxylic acid 49 wasinactive (>50 μM) possibly due to poor cell membrane penetration. Themodest activity of these compounds is encouraging given the simplicityand flexibility of their lower chain.

We therefore decided to introduce the more complex bottom part ofdictyostatin-1 lacking only the C9′-OH group. The synthesis of a lowerfragment more closely related to dictyostatin is shown in FIG. 10.Synthesis of the needed aldehyde 51 (FIG. 10) started from theintermediate 25, which was reduced to an alcohol with LiBH₄, followed byPMB acetal protection as in FIG. 4. Selective acetal opening producedalcohol 50, which was subjected to Dess-Martin oxidation to givealdehyde 27 (see FIG. 4). Wittig-Horner reaction, and removal of the TBSgroup with HF-pyridine gave a primary alcohol, which was oxidized toaldehyde 51.

Center part Wittig salt 21 (FIG. 3) was reacted with aldehyde 51 to givethe (Z)-olefin (FIG. 11). This was followed by selective PMP acetalopening with NaCNBH₃-TMSCl to yield a primary alcohol. The aldehydeobtained after Dess-Martin oxidation was again subjected to Wittigreaction with 33 to generate 52. Ester 52 was reduced to the alcoholwith DIBAL, followed by Dess-Martin oxidation and application of theStill (Z)-variant of the Wittig reaction to afford (E,Z) doublyunsaturated ester 53. Selective removal of the TBS groups wasaccomplished by exposure to 3N HCl-MeOH in THF (1:1). The resultingester was hydrolyzed by using 1N KOH in refluxing in EtOH. Finally, theYamaguchi lactonization protocol followed by DDQ deprotection gavemacrolactone 54, whose structure was confirmed by HMBC and other NMRexperiments. No isomerization of either of the dienes or the isolatedcis-alkenes was detected.

Compound 54 proved to be quite potent in terms of antiproliferativeactivity against human carcinoma cells (Table 2) showing a 50% growthinhibitory concentration against breast and ovarian cancer cells ofabout 1 μM. Furthermore compound 54 displaced [³H]paclitaxelstoichiometrically bound to microtubules at about ⅓rd the potency ofdiscodermolide.

TABLE 2 Human Cancer Cell Growth Inhibitory and Paclitaxel DisplacingProperties of Macrolactone Discodermolide Analogs Gl₅₀(μM)^(a)Displacement of MDA-MB-231 2008 [³H]paclitaxel (breast) (ovary) (%)^(c)43 27 ± 1 16 ± 1 18 ± 5 47 18 ± 1 22 ± 5 21 ± 2 48 26 ± 3 19 ± 2 17 ± 149 >50 >50 16 ± 3 54   1.4 ± 0.1^(b)   1.0 ± 0.1^(b) 27 ± 8discodermolide   0.016 ± 0.003^(b)   0.072 ± 0.005^(b) 64 ± 2 ^(a)Fiftypercent growth inhibitory concentration after 48 or 72 ^(b)hours ofcontinuous exposure (mean ± standard deviation; N = 4). ^(c)Percentdisplacement by 4 μM test agent of 2 μM [³H]paclitaxel bound tomicrotubules formed from 2 μM tubulin and 20 μM dideoxyGTP (N = 6, means± SD).

A second representative general strategy for the synthesis ofstereoisomers and close analogs of dictyostatin is shown in FIG. 12.Again the molecule is dissected such that every stereocenter can becontrolled and modified either by starting with an appropriate precursoror through an asymmetric reaction allowing access to both possibleisomers.

FIG. 13 summarizes the synthesis of the bottom fragment. (S)-Diethylmaleate was reduced and the resulting diol was converted to acetonide55. Reduction to the aldehyde and standard Evans aldol reaction gave 56.Reduction of this to the aldehyde and Wittig-Homer Emmons reaction gave57. Removal of the acetonide and silyation gave 58, which wasmono-desilylated to 59 and oxidized to aldehyde 60.

Coupling of the bottom fragment with the center fragment and elaborationare shown in FIG. 14. Wittig reaction of 21 (FIG. 3) and 60 proceededsmoothly to form 61, which was hydrolyzed and reduced to give 62. Aftertritylation to 63, DIBAL reduction gave 64. Oxidation and Wittig-Homerreaction produced 65, which was reduced to give 66 and hydrolyzed toacid 67. Activation of 67 as the mixed anhydride preceded conversion tothe oxazolidinone 68.

Introduction of the C16 stereocenter and introduction of the topfragment are shown in FIG. 15. Evans asymmetric alkylation to 69followed by removal of the chiral auxiliary by reduction gave 70.Separately, reagent 71 was made from the Evans oxazolindinone bydisplacement with LiCH₂P(O)(OMe)₂. Dess-Martin oxidation andHorner-Emmons olefination with 71 then gave 72, which was reduced withNiCl₂/NaBH₄ to 73. Now reduction with sodium borohydride gave a 2.8/1mixture of stereoisomers, which could be separated and converted to thefinal products independently. Silylation to 75 followed by DIBALreduction gave 76, which was converted to diene 77 as described above.Detriylation then gave 78.

Completion of the synthesis is shown in FIG. 16. Dess-Martin oxidationand Still-Gennari olefination gave 79 which was deprotected with DDQ to80. Saponification then gave the hydroxy acid 81 ready formacrocyclization. Treatment of 81 under the Yamaguchi protocol gave 82,which was finally deprotected to give the target product 83, an isomerof dictyostatin 1 called dictyostatin 5.

Representative methods to make analogs of the terminal diene fragmentare shown in FIG. 17. Alkene 84 was ozonized to give the aldehyde, whichwas subjected to a Wittig reaction to give analogs like 85.Alternatively, 84 can be converted to the Z-vinyl iodide 86, which canin turn be coupled with organometallic reagents like phenyl zinc iodideto give 87. This combination of olefination and organometallic andrelated coupling methods allows access to a wide variety of groups inthis position.

The versatility of the synthesis is illustrated by the preparations ofrepresentative additional fragments that can be used to makedictyostatin, its isomers and its analogs. FIG. 18 summarizes thesynthesis of a fully elaborated bottom fragment 92. Acetal 88, readilyprepared from (D)-malic acid, was silylated with t-butyldiphenylsilylchloride (TBDPSCl). Reductive cleavage of the acetal with DIBAL followedby Swern oxidation provided aldehyde 89. Reaction of 89 with theindicated Z-crotyl boronate according to Roush (See: Roush, W. R.;Hoong, L. K.; Palmer, M. A. J.; Straub, J. A.; Palkowitz, A. D.Asymmetric synthesis using tartrate modified allyl boronates. 2. Singleand double asymmetric reactions with alkoxy-substituted aldehydes, J.Org. Chem. 1990, 55, 4117–4126) provided 90 in 63% isolated yield. PMBprotection, ozonolysis and Wittig-Horner olefination then gave 91. Thiswas converted to the E/Z diene 92 by DIBAL reduction, Dess-Martinoxidation, Still-Gennari olefination and desilylation with HF/pyridine.

FIG. 19 shows the synthesis of two fragments with anti/anticonfigurations as assigned to dictyostatin 1 at C13–C15. Evan anti-aldolreaction of ent-4 and methacrolein (See: Evans, D. A.; Tedrow, J. S.;Shaw, J. T.; Downey, C. W. Diastereoselective magnesium halide-catalyzedanti-aldol reactions of chiral N-acyloxazolidinones. J. Am. Chem. Soc.2002, 124, 392–393) followed by TFA treatment gave 93 in 78% yield. Aminor diastereomer of 93 (about 16/1 ratio) was separated bychromatography. Silylation of 93 followed by hydroboration and oxidationprovided alcohol 94 in 75% yield alongside the lactone resulting fromcyclization of the terminal hydroxyl group with displacement of thechiral auxiliary (not shown, 10% yield). Silylation of 94 and reductivecleavage of the auxiliary provided 95, which was oxidized to 96 by theSwern method. Related aldehyde 98 was made by Roush allylboration ofent-17 (see 17 in FIG. 3) with the indicated E-crotylborate (mismatchedcase, 4/1 selectivity) to give 97, followed by reaction with PMBBr andozonolysis.

EXAMPLES

(4R)-4-Benzyl-3-[(2R,3R)-3-(tert-butyldimethylsilanyloxy)-2,4-dimethylpent-4-enoyl]oxazolidin-2-one (5). TBDMSOTf (3.44 mL, 15 mmol) was added toa stirred solution of aldol product (3.03 g, 10 mmol) and 1,6-lutidine(2.32 mL, 20 mmol) in CH₂Cl₂ (20 mL) at −78° C. and the mixture wasstirred for 2 h at ambient temperature. The reaction was quenched by theaddition of aqueous HCl (0.5 N, 50 mL). The resulting mixture wasextracted with CH₂Cl₂ and dried over MgSO₄ followed by the evaporationof solvent under reduced pressure. The product was purified by shortcolumn chromatography (hexane/EtOAc 9:1). Crude 5 was used withoutpurification.

(2S,3R,4S,5R)-2-Allyl-6-methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran(8). Diisobutylaluminum hydride (1.0 M in THF, 3.3 mL, 3.3 mmol) wasadded dropwise to a stirred solution of 7 (894 mg, 3 mmol) in anhydrousCH₂Cl₂ (30 mL) under an atmosphere of N₂ at −78° C. and the resultingmixture was stirred for an additional 1 h at −78° C. The reaction wasquenched by the careful addition of saturated aqueous potassium sodiumtartrate (50 mL) and stirred for 3 h at room temperature. Once theorganic and aqueous layers had separated, the aqueous layer wasextracted with CH₂Cl₂. The combined organic layer was washed with brineand dried over MgSO₄ followed by the evaporation of the solvent underreduced pressure. The crude lactol was used for the next reactionwithout further purification.

A solution of the lactol and CSA (0.3 mmol) in MeOH was stirred for 24 hat room temperature. The reaction mixture was diluted with EtOAc (100mL) and washed with saturated NaHCO₃ (50 mL). The aqueous layer wasextracted with EtOAc (50 mL). The combined organic layer was dried overMgSO₄. The solvent was removed under reduced pressure and the crudeproduct was used for the next reaction.

N,N-Diisopropylethylamine (7.5 mL) and chloromethyl methyl ether (1.13mL, 15 mmol) were added to a solution of the alcohol in CH₂Cl₂ (15 mL).The reaction mixture was heated to reflux and stirred overnight. Thereaction was quenched with aqueous saturated NaHCO₃ (50 mL) followed bywashing with brine. The aqueous layer was extracted with CH₂Cl₂ (2×50mL). The combined organic layer was dried over MgSO₄. The solvent wasremoved under reduced pressure and the crude product was purified bycolumn chromatography (hexane/EtOAc 7:3) to provide the pure anomers of8 (β, 33%; α, 32%). {tilde over (β)}8: IR (CHCl₃) 3053, 2985, 2305,1422, 1264 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.04 (m, 1H), 5.20–5.10 (m,2H), 4.81 (d, 1H, J=6.9 Hz), 4.73 (d, 1H, J=2.37 Hz), 4.67 (d, 1H, J=6.8Hz), 3.62 (m, 2H), 3.55 (s, 3H), 2.47 (m, 1H), 2.30 (m, 1H), 2.16 (m,1H), 1.85 (m, 1H), 1.03 (d, 3H, J=7.1 Hz), 0.97 (d, 3H, J=6.8 Hz); ¹³CNMR (75 MHz, CDCl₃) 135.1, 116.4, 101.3, 95.9, 81.9, 75.8, 56.4, 55.7,37.5, 37.3, 33.6, 13.2, 9.9; HRMS (EI) calcd for C₁₃H₂₄O₄ 244.1596,found 244.1592. {tilde over (α)}8: ¹H NMR (300 MHz, CDCl₃) δ 6.00 (m,1H), 5.22–5.12 (m, 2H), 4.83 (d, 1H, J=6.9 Hz), 4.69 (d, 1H, J=7.2 Hz),4.49 (d, 1H, J=1.8 Hz), 3.88 (dt, 1H, J=3.6, 8.8 Hz), 3.53 (t, 2H, J=3.6Hz), 3.48 (s, 3H), 2.45 (m, 1H), 2.28–2.11 (m, 3H), 1.94 (m, 1H), 1.12(d, 3H, J=7.3 Hz), 1.00 (d, 3H, J=6.9 Hz); ¹³C NMR (75 MHz, CDCl₃)135.2, 116.7, 103.4, 95.6, 78.7, 69.6, 55.7, 37.2, 35.8, 33.6, 15.9,13.5.

(2S,3R,4S,5R,6R)-3-(6-Methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl)propionaldehyde (9 a). BH₃.Me₂S (1 M in THF, 3 mL, 3 mmol) wasadded to a solution of 8 (488 mg, 2 mmol) in THF (10 mL) at 0° C. withstirring. The mixture was allowed to warm to room temperature andstirred for 3 h. The reaction was quenched with 2N aqueous NaOH (10 mL)followed by H₂O₂ (30%, 3 mL). After 1 h, the mixture was extracted withCH₂Cl₂ (3×20 mL). The combined organic layers were dried over anhydrousMgSO₄, evaporated and chromatographed (hexane/EtOAc 7:3) to yield 392 mg(75%) of alcohol as a colorless oil: IR (CHCl₃) 3103, 2982, 1375, 1240cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 4.83 (d, 1H, J=6.9 Hz), 4.76 (d, 1H,J=2.4 Hz), 4.69 (d, 1H, J=6.9 Hz), 3.75 (t, 2H, J=5.4 Hz), 3.61 (t, 1H,J=2.7 Hz), 3.57 (s, 3H), 2.58 (br s, 1H), 2.17 (m, 1H), 1.90–1.80 (m,4H), 1.04 (d, 3H, J=7.1 Hz), 0.97 (d, 3H, J=6.8 Hz); ¹³C NMR (75 MHz,CDCl₃) 101.5, 96.0, 82.0, 75.9, 62.8, 56.6, 55.8, 37.6, 34.0, 29.4,28.6, 13.4, 9.8; HRMS (EI) calcd for C₁₃H₂₆O₅ 262.1780, found 262.1792.

Pyridinium sulfurtrioxide (477 mg, 3 mmol) was added to a stirredsolution of alcohol (262 mg, 1 mmol) and N,N-diisopropylethylamine (0.52mL, 3 mmol) in anhydrous CH₂Cl₂ (6 mL) and DMSO (12 mL) at 0° C. Thereaction mixture was stirred at the ambient temperature for 1 h. Themixture was diluted with ethyl ether (50 mL) and washed with aqueous HCl(0.5 N, 50 mL) and brine (10 ml). The organic layer was dried overMgSO₄, filtered and concentrated under vacuum. Flash silica gel columnchromatography filtration (hexane/EtOAc 4:1) to remove SO₃-pyridineresidue provided the crude aldehyde 9 a as a colorless oil which wasused without further purification.

(4R)-4-Benzyl-3-[(2R,3S)-3-(tert-butyldimethylsilyloxy)-6-(4-methoxybenzyloxy)-2-methylhexanoyl]oxazolidin-2-one (11). Pyridinium sulfur trioxide(7.15 g, 45 mmol) was added to a stirred solution of themono-PMB-protected alcohol 10 (3.15 g, 15 mmol) andN,N-diisopropylethylamine (8.0 mL, 45 mmol) in anhydrous CH₂Cl₂ (15 mL)and DMSO (30 mL) at 0° C. The mixture was stirred at ambient temperaturefor 1 h, diluted with ethyl ether (300 mL) and washed with aqueous HCl(0.5 N, 200 mL), and brine. The separated organic layer was dried overMgSO₄. Filtration and concentration provided the crude aldehyde 10 as acolorless oil which was used for the next reaction without furtherpurification.

N,N-Diisopropylethylamine (1.9 mL, 11 mmol) was added to a solution ofpropionyloxazolidinone (2.33 g, 10 mmol) in anhydrous CH₂Cl₂ (110 mL) at0° C., followed by dropwise addition of Bu₂BOTf (1.0 M in CH₂Cl₂, 11 mL,11 mmol). The solution was stirred for 0.5 h at 0° C. Crude 10 inanhydrous CH₂Cl₂ (30 mL) was added at −78° C. The mixture was stirredfor 10 min at −78° C. followed by an additional 2 h at 0° C. Thereaction was quenched by addition of phosphate buffer, pH 7.0 (50 mL). Asolution of hydrogen peroxide (30%, 10 mL) in methanol (20 mL) was addedand the mixture was allowed to stir for 1 h at 0° C. After separation oforganic and aqueous layers, the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were dried over anhydrous MgSO₄, evaporatedand chromatographed (hexane/EtOAc 4:1) to yield the aldol adduct (3.83g, 87%) as a colorless oil: IR (CHCl₃) 3472, 2954, 2860, 2252, 1778,1691, 1383 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.48–7.36 (m, 7H), 7.01 (d,2H, J=8.7 Hz), 4.58 (m, 1H), 4.33 (s, 2H), 4.18 (br s, 1H), 3.94 (s,3H), 3.91 (m, 1H), 3.63 (t, 2H, J=6.0 Hz), 3.40 (dd, 1H, J=3.2, 13.3Hz), 3,37 (br s, 1H), 2.90 (dd, 1H, J=3.8, 13.3 Hz), 1.97–1.59 (m, 5H),1.40 (d, 3H, J=7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) 177.3, 159.2, 153.1,135.3, 130.6, 129.5, 129.3, 129.0, 127.4, 113.8, 72.5, 71.5, 69.9, 66.2,55.2, 42.7, 37.7, 31.3, 26.4, 14.3, 11.1; HRMS (EI) calcd for C₂₅H₃₁NO₆441.2151, found 441.2162.

TBDMSOTf (1.7 mL, 7.5 mmol) was added to a stirred solution of the abovealcohol (2.20 g, 5 mmol) and 2,6-lutidine (1.2 mL, 10 mmol) in CH₂Cl₂(50 mL) at −78° C. and the mixture was stirred for 2 h at ambienttemperature. The reaction was quenched by addition of aqueous HCl (0.5N, 100 mL). The reaction mixture was extracted with CH₂Cl₂ and driedover MgSO₄ followed by the evaporation of the solvent under reducedpressure. The product was purified by column chromatography(hexane/EtOAc 9:1) to yield 11: IR (CHCl₃) 3020, 2955, 2858, 1779, 1362,1211 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.45–7.36 (m, 7H), 7.00 (d, 2H,J=8.7 Hz), 4.70 (m, 1H), 4.56 (s, 2H), 4.27–4.15 (m, 3H), 4.04 (dd, 1H,J=5.4, 6.8), 3.91 (s, 3H), 3.60 (m, 3H), 3.40 (dd, 1H, J=3.0, 13.2 Hz),2.90 (dd, 1H, J=9.5, 13.2 Hz), 1.80 (br m, 4H), 1.38 (d, 3H, J=6.8 Hz),1.05 (s, 9H), 0.21 (s, 3H), 0.17 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) 175.4,159.2, 153.2, 135.5, 130.9, 129.6, 129.3, 129.0, 127.4, 113.8, 72.9,72.5, 70.2, 66.1, 55.9, 55.3, 42.8, 37.7, 32.1, 26.0, 25.2, 18.2, 12.2,−3.92, −4.65; LRMS (ESI) 578.3 (M+Na).

(2S,3S)-3-(tert-Butyldimethylsilanyloxy)-6-(4-methoxybenzyloxy)-2-methylhexan-1-ol. Lithium borohydride (2.0 M in THF, 5 mL, 10 mmol) was addeddropwise to a stirred solution of 11 (2.77 g, 5 mmol) and methanol (0.4mL, 10 mmol) in anhydrous THF (20 mL) under an atmosphere of N₂ at 0° C.The mixture was stirred for 20 min at 0° C. and then warmed to ambienttemperature. After 3 h at room temperature, the reaction was quenchedwith aqueous NH₄Cl (100 mL) and extracted with CH₂Cl₂ (3×20 mL). Thecombined organic layers were dried over anhydrous MgSO₄, evaporated andchromatographed (hexane/EtOAc 7:3) to yield the alcohol (1.48 g, 78%) asa colorless oil: IR (CHCl₃) 2948, 2856, 2302, 1612, 1265 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 7.27 (d, 2H, J=8.5 Hz), 7.00 (d, 2H, J=8.5 Hz), 4.43(s, 2H), 3.78 (s, 3H), 3.67 (dd, 1H, J=8.6, 10.5 Hz), 3.51–3.41 (m, 3H),2.78 (br s, 1H), 1.94 (m, 1H), 1.72–1.49 (m, 4H), 0.90 (s, 9H), 0.81 (d,3H, J=7.0 Hz), 0.09 (s, 3H), 0.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)159.2, 130.6, 129.3, 113.8, 75.4, 72.6, 70.1, 65.8, 55.9, 55.3, 39.7,29.1, 26.6, 25.9, 18.0, 12.1, −4.28, −4.38; LRMS (ESI) 405.2 (M+Na).

(4R)-4-Benzyl-3-[(2R,3S,4R,5S)-5-(tert-butyldimethylsilanyloxy)-3-hydroxy-8-(4-methoxybenzyloxy)-2,4-dimethyloctanoyl]oxazolidin-2-one(12). Pyridinium sulfur trioxide (2.38 g, 15 mmol) was added to astirred solution of the above TBS-protected alcohol (1.91 g, 5 mmol) andN,N-diisopropylethylamine (2.65 mL, 15 mmol) in anhydrous CH₂Cl₂ (5 mL)and DMSO (10 mL) at 0° C. The mixture was stirred at the ambienttemperature for 1 h, diluted with ethyl ether (100 mL), washed withaqueous HCl (0.5 N, 100 mL) and brine, then dried over MgSO₄. Filtrationand concentration provided the crude aldehyde as a colorless oil whichwas used without further purification.

N,N-Diisopropylethylamine (0.97 mL, 5.5 mmol) was added to a solution ofpropionyloxazolidinone (1.16 g, 5 mmol) in anhydrous CH₂Cl₂ (11 mL) at0° C., followed by dropwise addition of Bu₂BOTf (1.0 M in CH₂Cl₂, 5.5mL, 5.5 mmol). The solution was stirred for 0.5 h at 0° C. A solution ofcrude aldehyde 12 from above in anhydrous CH₂Cl₂ (10 mL) was added at−78° C. The reaction mixture was stirred for 10 min at −78° C. then for2 h at 0° C. The reaction mixture was quenched with phosphate buffer, pH7.0 (50 mL). A solution of hydrogen peroxide (30%, 10 mL) in methanol(20 mL) was slowly added and the mixture was stirred for 1 h. After theseparation of organic and aqueous layers, the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were dried overanhydrous MgSO₄, evaporated and chromatographed (hexane/EtOAc 4:1) toyield desired compound (2.29 g, 75%) as a colorless oil: IR (CHCl₃)2949, 2855, 2253, 1779, 1692, 1463 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.33–7.19 (m, 7H), 7.01 (d, 2H, J=8.1 Hz), 4.42 (m, 1H), 4.44 (s, 2H),4.16 (d, 1H, J=5.1 Hz), 4.01 (m, 1H), 3.95 (t, 1H, J=6.3 Hz), 3.85 (m,1H), 3.79 (s, 3 H), 3.43 (br s, 2H), 3.24 (br s, 1H), 3.20 (dd, 1H,J=2.4, 13.5 Hz), 2.77 (dd, 1H, J=9.6, 13.2 Hz), 1.56–1.31 (m, 5H), 1.32(d, 3H, J=6.9 Hz), 0.95 (d, 3H, J=6.9 Hz), 0.89 (s, 9H), 0.08 (s, 6H);¹³C NMR (75 MHz, CDCl₃) 177.2, 159.2, 152.7, 135.1, 130.6, 129.5, 129.3,129.0, 127.5, 113.8, 76.8, 74.2, 72.6, 70.0, 66.1, 55.3, 55.0, 40.6,38.1, 37.8, 31.3, 25.9, 18.1, 13.2, 7.4, −3.5, −4.6; HRMS (EI) calcd forC₃₄H₅₁NO₇Si 613.3435, found 613.3427.

(4R)-4-Benzyl-3-[(2R,3S,4R,5S)-5-(tert-butyldimethylsilanyloxy)-8-(4-methoxybenzyloxy)-3-methoxymethoxy-2,4-dimethyloctanoyl]oxazolidin-2-one(13). N,N-Diisopropylethylamine (7.5 mL) and chloromethyl methyl ether(mL, 9 mmol) were added to a solution of the alcohol from above (1.83 g,3 mmol) in CH₂Cl₂ (15 mL). The mixture was stirred at reflux overnight.The reaction was quenched with aqueous sat'd NaHCO₃ (50 mL) and washedwith brine. The aqueous layer was extracted with CH₂Cl₂ (2×50 mL). Thecombined organic layer was dried over MgSO₄. The solvent was removedunder reduced pressure and the crude product was purified by columnchromatography (hexane/EtOAc 4:1) to provide the pure product in 92%yield: IR (CHCl₃) 3020, 2862, 1781, 1215 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.36–7.27 (m, 7H), 6.94 (d, 2H, J=8.7 Hz), 4.75 (s, 2H), 4.69 (m, 1H),4.53 (s, 2H), 4.19 (dd, 1H, J=10.2, 15.0 Hz), 3.97 (dd, 1H, J=3.0, 6.6Hz), 3.84 (br s, 4H), 3.43 (br t, 2H), 3,45 (s, 3H), 3.30 (dd, 1H,J=3.0, 13.2 Hz), 2.77 (dd, 1H, J=9.3, 13.5 Hz), 1.81–1.75 (m, 5H), 1.36(d, 3H, J=6.9 Hz), 1.02 (d, 3H, J=6.9 Hz), 0.98 (s, 9H), 0.16 (s, 3H),0.15 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) 175.5, 159.1, 153.0, 135.4, 131.0,129.5, 129.2, 129.0, 127.4, 113.7, 98.3, 80.3, 76.9, 73.2, 72.3, 70.5,66.0, 56.3, 55.6, 55.2, 41.7, 40.8, 37.6, 30.6, 26.1, 24.2, 18.3, 14.0,10.5, −3.9, −4.3; HRMS (EI) calcd for C₃₄H₅₀NO₇Si (M−CH₂OCH₃) 612.3356,found 612.3367 (M−CH₂OCH₃).

6-[(3R,4S,5S,6S)-3-(4-Methoxybenzyloxy)propyl]-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-one(14). HF-pyridine (6 mL) was added to a solution of 13 (1.31 g, 2 mmol)in MeOH (20 mL) and pyridine (10 mL) at 0° C. The mixture was stirred atroom temperature for 48 h, diluted with EtOAc (100 mL), washed withaqueous HCl (0.5 N, 2×50 mL) and with brine. The aqueous layer wasextracted with EtOAc (50 mL). The combined organic layer was dried overanhydrous Na₂SO₄. The solvent was removed under reduced pressure, andthe crude product was purified by column chromatography (hexane/EtOAc4:1) to provide the pure product in 83% yield: IR (CHCl₃) 3020, 2952,1730, 1513, 1216 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.24 (d, 2H, J=8.7 Hz),6.87 (d, 2H, J=8.7 Hz), 4.72 (d, 1H, J=7.2 Hz), 4.60 (d, 1H, J=7.2 Hz),4.48 (m, 1H), 4.43 (s, 2H), 3.80 (s, 3H), 3.50–3.39 (m, 2H), 3.39 (s,3H), 3.26 (dd, 1H, J=1.1, 7.0 Hz), 2.58 (t, 1H, J=6.9 Hz), 2.03 (d, 1H,J=7.5 Hz), 1.81–1.63 (m, 4H), 1.31 (d, 3H, J=6.7 Hz), 0.91 (d, 3H, J=7.3Hz); ¹³C NMR (75 MHz, CDCl₃) 174.1, 159.2, 130.5, 129.3, 113.8, 95.5,82.6, 76.7, 72.6, 69.4, 55.9, 55.3, 40.5, 38.4, 28.6, 26.0, 14.4, 11.9,−3.9; HRMS (EI) calcd for C₂₀H₃₀O₆ 366.2042, found 366.2050.

2-Methoxy-6-[(3R,4S,5S,6S)-3-(4-methoxybenzyloxy)propyl]4-methoxymethoxy-3,5-dimethyltetrahydropyran(15). Diisobutylaluminum hydride (1.0 M in THF, 2.2 mL, 2.2 mmol) wasadded dropwise to a stirred solution of 14 (732 mg, 2 mmol) in anhydrousCH₂Cl₂ (20 mL) under an atmosphere of N₂ at −78° C. and the mixture wasstirred for 1 h at −78° C. The reaction was quenched by the carefuladdition of aqueous sat'd potassium sodium tartrate (50 mL) and stirringfor 3 h at room temperature. Once the organic and aqueous layersseparated, the aqueous layer was extracted with CH₂Cl₂. The combinedorganic layer was washed with brine and dried over MgSO₄ followed by theevaporation of solvent under reduced pressure. The crude lactol obtainedwas used without further purification.

A solution of the lactol and PPTS (0.2 mmol) in MeOH was stirred for 15h at room temperature. The reaction mixture was diluted with EtOAc (100mL) and washed with sat'd aqueous NaHCO₃ (50 mL). The aqueous layer wasextracted with EtOAc (50 mL). The combined organic layer was dried overMgSO₄. The solvent was removed under reduced pressure, and the crudeproduct was purified by column chromatography (hexane/EtOAc 7:3) toprovide the pure product each anomer 15 (p, 64%; a, 26%). β-15: IR(CHCl₃) 3020, 2858, 2299, 1514, 1216 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.35 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=8.7 Hz), 4.76 (d, 2H, J=3.0 Hz),4.52 (s, 2H), 4.37 (d, 1H, J=4.6 Hz), 4.09 (m, 1H), 3.89 (s, 2H), 3.57(m, 2H), 3.47 (s, 3H), 3.32 (t, 1H, J=5.7 Hz), 1.89–1.71 (m, 6H), 1.16(d, 3H, J=7.2 Hz), 1.07 (d, 3H, J=7.9 Hz); ¹³C NMR (75 MHz, CDCl₃)159.2, 130.7, 129.3, 113.8, 103.2, 96.3, 82.0, 72.6, 69.9, 69.3, 55.7,55.3, 39.1, 38.0, 27.1, 26.5, 16.0, 13.1; HRMS (EI) calcd for C₂₁H₃₄O₆382.2353, found 382.2355. α-15: ¹H NMR (300 MHz, CDCl₃) δ 7.34 (d, 2H,J=8.7 Hz), 6.95 (d, 2H, J=8.7 Hz), 4.72 (s, 2H), 4.70 (d, 1H, J=2.8 Hz),4.52 (s, 2H), 4.09 (br m, 4H), 3.67 (br s, 1H), 3.56 (m, 5H), 3.44 (s,3H), 2.08–1.54 (m, 6H), 1.11 (d, 3H, J=3.0 Hz), 1.08 (d, 3H, J=2.9 Hz).

(2S,3S,4S,5R,6R)-3-(6-Methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl)propionaldehyde (9 b). A mixture of PMB ether 15 (458 mg, 1.2mmol) and palladium (10% Pd/C, 5 mg) was stirred in EtOAc (12 mL) for 3h at room temperature under an H₂ atmosphere (balloon), filtered andconcentrated to yield the debenzylated alcohol which was used withoutfurther purification.

The crude alcohol in CH₂Cl₂ (12 mL) was treated with Dess-Martinperiodinane (636 mg, 1.5 mmol) at room temperature. The reaction wasquenched with saturated aqueous NaHCO₃ (20 mL). The aqueous layer wasextracted with CH₂Cl₂ (10 mL×2) and the combined extracts were driedover anhydrous MgSO₄. Filtration and concentration followed by shortflash column chromatography (hexane/EtOAc 4:1) provided 274 mg (88%) ofthe crude aldehyde as a colorless oil which was used without furtherpurification: ¹H NMR (500 MHz, CDCl₃) δ 9.80 (s, 1H), 4.67 (dd, 2H,J=7.0, 12.5 Hz), 4.27 (d, 1H, J=4.5 Hz), 3.99 (dd, 1H, J=3.5, 4.0 Hz),3.36 (s, 6H), 3.24 (t, 1H, J=6.0 Hz), 2.61 (m, 1H), 2.52 (m, 1H), 1.83(m, 3H), 1.68 (m, 1H), 1.05 (d, 3H, J=7.0 Hz), 1.01 (d, 3H, J=7.5 Hz).

(2S,3R,4S)-5-(tert-Butyldimethylsilanyloxy)-2,4-dimethylpentane-1,3-diol.MeOH (0.51 mL) and LiBH₄ (2.0 M in THF, 6.2 mL, 12.4 mmol) were addeddropwise to a stirred solution of aldol product 18 [22] (5.38 g, 12.3mmol) in THF (50 mL) at 0° C. After stirring for 1 h at 0° C., saturatedaqueous sodium potassium tartrate (70 mL) was added. The mixture wasallowed to warm room temperature and extracted with CH₂Cl₂ (2×50 mL).The combined organic layer was washed with brine (40 mL), dried overanhydrous MgSO₄, concentrated and flash column chromatographed(hexane/EtOAc 4:1) to yield 2.99 g (92%) of the desired product as acolorless oil: IR (CHCl₃) 3409, 2958, 2927, 2853, 2878, 1469, 1385,1361, 1252, 1082, 838, 773 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 4.45 (br s,1H), 3.54 (br s, 1H), 1.92 (m, 1H), 1.83 (m, 1H), 1.06 (d, 3H, J=6.98Hz), 1.00 (s, 9H), 0.84 (d, 3H, J=6.88 Hz), 0.19 (s, 6H); ¹³C NMR (75MHz, CDCl₃) 79.3, 69.7, 67.5, 37.4, 36.6, 25.9, 18.1, 12.8, 8.9, −5.5,−5.6; LRMS (EI) 263 (M+H); HRMS (EI) calcd for C₁₃H₃₀O₃Si 263.2042,found 263.2042; [α]²⁰ _(D) +35.5 (c 0.85, CHCl₃).

(2S)-tert-Butyl-{(4R,5S)-2-[2-(4-methoxyphenyl)-5-methyl[1,3]dioxan-4-yl]propoxy}dimethylsilane(20). A solution of the above diol (2.8 g, 10.7 mmol), p-anisaldehydedimethylacetal (2.0 mL, 11.7 mmol) and PPTS (0.27 g, 1.1 mmol) inbenzene was heated to reflux for 3 h. The solvent was evaporated underreduced pressure and the residue was purified by column chromatography(hexane/EtOAc 9:1) to give 20 (2.6 g, 6.8 mmol) in 64% yield: IR (CHCl₃)2955, 2927, 2853, 1617, 1518, 1459, 1382, 1157, 1101, 1033, 826 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.49 (m, 2H), 6.98 (m, 2H), 5.50 (m, 2H), 3.89(s, 3H), 3.82 (dd, 1H, J=10.9, 4.9 Hz), 3.76 (dd, 2H, J=8.1, 2.8 Hz),1.87 (m, 1H), 1.71 (m, 1H), 1.23 (d, 3H, J=7.6 Hz), 1.00 (d, 3H, J=6.5Hz); ¹³C NMR (75 MHz, CDCl₃) 160.1, 132.1, 127.6, 113.8, 113.7, 101.9,80.1, 74.3, 65.2, 64.3, 55.5, 37.4, 30.0, 26.3, 26.2, 18.7, 12.4, 11.3,−5.0, −5.1; LRMS (EI) 323, 207, 187, 157, 145, 121, 75; HRMS (EI) calcdfor C₂₁H₃₆O₄Si₁ 323.1678 (M−^(t)Bu), found 323.1694 (M−^(t)Bu); [α]²⁰_(D) −33.6 (c 1.24, CHCl₃).

(2S)-2-[(4R,5S)-2-(4-Methoxyphenyl)-5-methyl[1,3]dioxan-4-yl]propan-1-ol.TBAF (1.0M in THF, 22 mL, 22 mmol) was added to a solution of 20 (2.8 g,7.3 mmol) in THF (70 mL) at room temperature and the mixture was stirredfor 2 h. The mixture was diluted with ethyl ether (100 mL) and brine.The organic layer was dried over MgSO₄. Filtration and concentrationfollowed by flash column chromatography (hexane/EtOAc 7:3) providedalcohol (1.95 g, 7.2 mmol) as a yellow oil: IR (CHCl₃) 3428, 2964, 2930,2835, 1614, 1512, 1463, 1391, 1249, 1098, 1027 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 7.38 (m 2H), 6.87 (m, 2H), 5.48 (s, 1H), 4.11 (dd, 2H, J=4.6,4.5 Hz), 3.75 (s, 3H), 3.73 (m, 2H), 3.52 (apparent t, 1H, J=11.1 Hz),2.08 (m, 1H), 2.00 (m, 1H), 1.04 (d, 3H, J=7.1 Hz), 0.77 (d, 3H, J=6.7Hz); ¹³C NMR (75 MHz, CDCl₃) 160.0, 131.5, 127.4, 113.6, 101.6, 83.4,73.9, 66.3, 55.2, 36.8, 30.4, 11.9, 9.9; LRMS (EI) 266, 207, 177, 153,135, 77; HRMS (EI) calcd for C₁₅H₂₂O₄ 266.1518, found 266.1517; [α]²⁰_(D) −4.8 (c 0.67, CHCl₃).

(2S)-{2-[(4R,5S)-2-(4-Methoxyphenyl)-5-methyl[1,3]dioxan-4-yl]propyl}triphenyl-□5-phosphane iodide (21). I2 (4.48 g, 17.6mmol) was added at 0° C. to a solution of the alcohol from above (2.35g, 8.82 mmol) in CH₂Cl₂ (110 mL) containing imidazole (1.32 g, 19.4mmol) and triphenylphosphine (4.63 g, 17.6 mmol). The resulting slurrywas stirred for 1 h and quenched with saturated aqueous Na₂S₂O₃ (10 mL).The organic layer was separated and washed with water (20 mL), brine anddried over anhydrous MgSO₄. The solvent was evaporated under reducedpressure and the residue was purified by column chromatography(hexane/EtOAc 9:1) to give the pure iodide.

The iodide was quickly dissolved in benzene (44 mL), PPh₃ was added(11.5 g, 44.1 mmol) and the mixture heated to reflux for 36 h. Thereaction mixture was cooled to room temperature and anhydrous ethylether (50 mL) was added, whereupon a white solid precipitated.Filtration followed by washing of the solid with ethyl ether (10 mL)provided the phosphonium salt (4.5 g) as a white foam: IR (CHCl₃) 3054,2961, 2909, 1611, 1515, 1435, 1246, 1107, 993, 752 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 7.55 (m, 9H), 7.37 (m, 6H), 7.21 (m, 2H), 6.65 (m, 1H),5.41 (s, 1H), 3.95 (d, 1H, J=10.2 Hz), 3.68 (d, 2H, J=12.3 Hz), 3.54 (s,3H), 3.26 (m, 1H), 1.85 (m, 1H), 1.46 (apparent d, 1H, J=6.5 Hz), 0.78(d, 3H, J=6.8 Hz), 0.44 (d, 3H, J=6.6 Hz); ¹³C NMR (75 MHz, CDCl₃)160.0, 135.2, 135.1, 133.7, 133.5, 131.1, 130.5, 130.4, 127.9, 119.0,117.9, 113.5, 101.9, 82.3, 82.1, 73.2, 55.5, 30.7, 29.2, 25.3, 15.7,10.4 HRMS (EI) calcd for C₃₃H₃₆O₃P 511.2402, found 511.2428; [α]²⁰ _(D)+31.9 (c 0.78, CHCl₃).

(4R,5R)-tert-Butyl-{3-[2-(4-methoxyphenyl)-5-methyl[1,3]dioxan-4-yl]propoxy}dimethylsilane(26). Lithium borohydride (2.0 M in THF, 25 mL, 50 mmol) was addeddropwise to a stirred solution of 25 (8.70 g, 20 mmol) and MeOH (1.61mL, 40 mmol) in anhydrous THF (100 mL) under an atmosphere of N₂ at 0°C. The mixture was stirred for 20 min at 0° C. and then warmed toambient temperature. After 2 h at room temperature, the reaction wasquenched with aqueous NH₄Cl (100 mL) and extracted with CH₂Cl₂ (3×10mL). The combined organic layers were dried over anhydrous MgSO₄,evaporated and chromatographed (hexane/EtOAc 7:3) to yield 4.97 g (95%)of the diol as a colorless oil.

A solution of the diol (2.62 g, 10 mmol), anisaldehyde dimethyl acetal(2.00 g, 11.0 mmol), and PPTS (0.1 equiv) in benzene was stirred for 15h at reflux. The reaction mixture was quenched with aqueous sat'd NaHCO₃(50 mL) followed by washing with water. The aqueous layer was extractedwith ethyl ether (2×50 mL). The combined organic layer was dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas purified by column chromatography (hexane/EtOAc 7:3) to provide thepure 26 in 72% yield: IR (CHCl₃) 2992, 1742, 1373, 1240 cm⁻¹; ¹H NMR(500 MHz, CDCl₃) δ 7.43 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=8.4 Hz), 5.45(s, 1H), 4.08 (dd, 2H, J=10.5, 29.9 Hz), 3.90 (br s, 1H), 3.80 (s, 3H),3.67 (m, 2H), 1.67–1.50 (m, 5H), 1.17 (d, 3H, J=7.0 Hz), 0.90 (s, 9H),0.06 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) 159.9, 131.6, 127.4, 113.6, 101.7,79.7, 73.9, 63.1, 55.3, 31.8, 29.3, 28.7, 26.0, 18.4, 11.1, −5.1; LRMS(ESI) 402.68 (M+Na).

(4R,5S)-4-{(1S,2Z)-5-[(2S,3R,4S,5R,6R)-6-Methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl]-1-methylpent-2-enyl}-2-(4-methoxyphenyl)-5-methyl[1,3]dioxane(35). NaHMDS (1.0 M in THF, 1.1 mL, 1.1 mmol) was slowly added to asolution of the salt 21 (701 mg, 1.1 mmol) in dry THF (2.2 mL) at 0° C.The resulting red solution was stirred at room temperature for 20 min.The mixture was cooled to −78° C. and a solution of the aldehyde 9 a(260 mg, 1 mmol) in THF (1 mL×2) was added dropwise. The mixture wasstirred for 20 min at −78° C. and then warmed to room temperature. After4 h at room temperature, the mixture was quenched with saturated NH₄Cl(10 mL) and extracted with CH₂Cl₂ (3×10 mL). The combined organic layerswere dried over anhydrous MgSO₄, evaporated and chromatographed(hexane/ether 9:1) to yield 329 mg (67%) of 35 as a colorless oil: IR(CHCl₃) 2922, 2866, 2628, 2350, 1740, 1516 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)δ 7.45 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=8.4 Hz), 5.46 (m, 2H), 5.30 (t,1H, J=9.9 Hz), 4.77 (d, 1H, J=6.9 Hz), 4.70 (d, 1H, J=1.8 Hz), 4.63 (d,1H, J=6.9 Hz), 4.06 (br d, 1H, J=2.1 Hz), 3.80 (s, 3H), 3.54 (m, 3H),3.43 (s, 3H), 3.32 (s, 3H), 2.77 (m, 1H), 2.31 (dd, 2H, J=7.5, 14.7 Hz),1.79–1.55 (m, 4H), 1.22 (d, 3H, J=6.6 Hz), 1.02 (d, 3H, J=7.2 Hz), 0.96(d, 3H, J=6.9 Hz), 0.86 (d, 3H, J=6.9 Hz); ¹³C NMR (75 MHz, CDCl₃) δ159.7, 133.4, 131.8, 130.1, 127.3, 113.3, 101.5, 101.3, 95.9, 83.5,82.0, 75.2, 73.9, 56.4, 55.7, 55.2, 37.6, 34.2, 33.6, 33.0, 30.0, 23.4,16.1, 13.3, 11.2, 9.9; HRMS (EI) calcd for C₂₇H₄₀O₆ 460.2824, found460.2846.

(4R,5S)-4-{(1S,2Z)-5-[(2S,3S,4S,5R,6R)-6-Methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl]-1-methylpent-2-enyl}-2-(4-methoxyphenyl)-5-methyl[1,3]dioxane(36). NaHMDS (1.0 M in THF, 1.1 mL, 1.1 mmol) was slowly added to asolution of the salt 21 (0.70 g, 1.1 mmol) in dry THF (2 mL) at 0° C.The resulting red solution was stirred at room temperature for 20 min.The mixture was cooled to −78° C. and a solution of the aldehyde 9 b(260 mg, 1 mmol) in THF (1 mL) was added dropwise. The mixture wasstirred for 20 min at −78° C. and then warmed to room temperature. After4 h at room temperature, the reaction was quenched with saturated NH₄Cl(10 mL) and extracted with CH₂Cl₂ (3×10 mL). The combined organic layerswere dried over anhydrous MgSO₄, evaporated and chromatographed(hexane/ether 9:1) to yield 329 mg (67%) of 36 as a colorless oil: IR(CHCl₃) 2922, 2866, 2628, 2350, 1740, 1516 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)δ 7.48 (d, 2H, J=9.0 Hz), 6.91 (d, 2H, J=9.0 Hz), 5.46 (m, 2H), 5.32 (t,1H, J=9.6 Hz), 4.73 (s, 2H), 4.31 (d, 1H, J=5.4 Hz), 4.07 (br s, 2H),3.81 (s, 1H), 3.57 (dd, 1H, J=1.8, 9.6 Hz), 3.45 (s, 3H), 3.43 (s, 3H),3.20 (t, 1H, J=6.6 Hz), 2.77 (m, 1H), 2.31–2.17 (m, 2H), 1.90–1.62 (m,4H), 1.24–0.98 (m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 159.7, 133.7, 131.7,129.4, 127.2, 113.4, 102.8, 101.5, 96.6, 83.5, 82.2, 73.9, 70.0, 55.7,55.2, 39.8, 38.4, 33.6, 30.0, 29.9, 24.3, 15.9, 15.5, 13.2, 11.1; HRMS(EI) calcd for C₂₇H₄₀O₆ (M−HOCH₃) 460.2824, found 460.2846.

(2R,3S,4S,5Z)-3-(4-Methoxybenzyloxy)-8-[(2S,3R,4S,5R,6R)-6-methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl]-2,4-dimethyloct-5-enal(37). DIBAL (1.0 M in hexane, 2.1 mL, 2.1 mmol) was added dropwise to asolution of the acetal 35 (329 mg, 0.67 mmol) in dry CH₂Cl₂ (6.7 mL) at0° C. After stirring for 2 h, the reaction was quenched with saturatedaqueous sodium tartrate (20 mL) followed by vigorously stirring forseveral hours. The aqueous phase was extracted with CH₂Cl₂ (3×10 mL) andthe combined organic layers were washed with brine (10 mL). The residueobtained after drying over MgSO₄ and evaporation under vacuum wasdissolved in anhydrous CH₂Cl₂ (6 mL) and DMSO (12 mL), treated withN,N-diisopropylethylamine (0.52 mL, 3 mmol), cooled to 0° C. and treatedwith pyridinium sulfur trioxide (477 mg, 3 mmol). The reaction mixturewas stirred at ambient temperature for 1 h, diluted with ethyl ether (50mL) and washed with aqueous HCl (0.5 N, 50 mL) and brine (10 ml). Theseparated organic layer was dried over MgSO₄. Filtration andconcentration followed by short flash column chromatography(hexane/EtOAc 4:1) provided the crude aldehyde 37 (270 mg, 0.55 mmol) asa colorless oil which was used without further purification.

(2R,3S,4S,5Z)-3-(4-Methoxybenzyloxy)-8-[(2S,3S,4S,5R,6R)-6-methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl]-2,4-dimethyloct-5-enal(38). DIBAL (1.0 M in hexane, 2.1 mL, 2.1 mmol) was added dropwise to asolution of the acetal 36 (329 mg, 0.67 mmol) in dry CH₂Cl₂ (6.7 mL) at0° C. After the mixture was stirred for 2 h, the reaction was quenchedwith saturated aqueous sodium tartrate (20 mL) followed by vigorousstirring for several hours. The aqueous phase was extracted with CH₂Cl₂(3×10 mL) and the combined organic layers were washed with brine (10mL). After drying over MgSO₄ and evaporation under vacuum, the residuewas used for the next reaction without further purification. The crudealcohol in CH₂Cl₂ (13 mL) was treated with Dess-Martin periodinane(340.8 mg, 0.80 mmol). After the reaction was complete, the mixture wasquenched with saturated NaHCO₃ (20 mL). The aqueous layer was extractedwith CH₂Cl₂ (2×10 mL) and the combined extracts were dried overanhydrous MgSO₄. Filtration and concentration followed by short flashcolumn chromatography filtration (hexane/EtOAc 9:1) provided crudealdehyde 38 (267 mg, 81%) as a colorless oil which was used withoutfurther purification.

(2S,3R)-6-(tert-Butyldimethylsilanyloxy)-3-(4-methoxybenzyloxy)-2-methylhexanal(27). DIBAL (1.0 M in THF, 15 mL, 15 mmol) was added dropwise to astirred solution of 26 (1.90 g, 5 mmol) in anhydrous CH₂Cl₂ (50 mL)under an atmosphere of N₂ at 0° C. and the mixture was stirred for 1 hat 0° C. The reaction was quenched by the careful addition of aqueoussat'd potassium sodium tartrate (100 mL) and stirring for 3 h at roomtemperature. Once the aqueous and organic layers separated, the aqueouslayer was extracted with CH₂Cl₂. The combined organic layer was washedwith brine and dried over MgSO₄ followed by the evaporation of thesolvent under reduced pressure. The crude alcohol (1.56 g, 4.1 mmol) wasused without further purification.

Pyridinium sulfur trioxide (2.38 g, 15 mmol) was added to a stirredsolution of the crude alcohol from above and diisopropylethylamine (2.6mL, 15 mmol) in anhydrous CH₂Cl₂ (10 mL) and DMSO (20 mL) at 0° C. Themixture was stirred at ambient temperature for 1 h. After the reactionwas complete, the mixture was diluted with ethyl ether (100 mL) andwashed with aqueous HCl (0.5 N, 100 mL) and brine (100 ml). Theseparated organic layer was dried over MgSO₄. Filtration andconcentration followed by short flash column chromatography filtration(hexane/EtOAc 4:1) to remove SO₃-pyridine provided the crude aldehyde 27as a colorless oil which was used without further purification.

(2R,3R,4R,5R)-8-(tert-Butyldimethylsilanyloxy)-3-hydroxy-5-(4-methoxybenzyloxy)-2,4-dimethyloctanoic acid, 2,6-dimethylphenyl ester (29). LDA (2M inTHF, 3.1 mL, 6.2 mmol) was added to a solution of 2,6-dimethylphenoxypropionate (1.10 g, 6.2 mmol) in anhydrous THF (12.4 mL) at −78° C.,followed by stirring for 1 h at −78° C. The crude aldehyde 27 (4.1 mmol)from above dissolved in anhydrous THF (10 mL) was added slowly at −78°C. After 2 h at room temperature, the mixture was quenched withsaturated aqueous NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3×10 mL). Thecombined organic layer was dried over anhydrous MgSO₄, evaporated andchromatographed (hexane/EtOAc 4:1) to yield 29 (1.67 g, 2.99 mmol) as acolorless oil: IR (CHCl₃) 3120, 2857, 1744, 1514, 1216, 1099 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.26 (d, 2H, J=8.4 Hz), 6.87 (d, 2H, J=8.4 Hz),4.62 (d, 1H, J=11.1 Hz), 4.40 (d, 1H, J=11.1 Hz), 4.06 (d, 1H, J=6.8Hz), 3.79 (s, 3H), 3.66–3.61 (m, 3H), 2.89 (m, 1H), 2.19 (s, 6H), 1.86(m, 2H), 1.55 (m, 3H); 1.27 (d, 3H, J=6.8 Hz), 1.01 (d, 3H, J=6.9 Hz),0.93 (s, 9H), 0.07 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 173.5, 159.2,148.0, 130.0, 129.9, 129.4, 128.4, 125.6, 113.8, 83.5, 70.7, 62.9, 55.1,44.0, 35.6, 28.7, 26.6, 25.8, 18.2, 16.3, 14.2, 5.7, −5.3; HRMS (EI)calcd for C₃₂H₅₀O₆Si 558.3377, found 558.3392.

(2S,3S,4R,5R)-3,8-Bis-(tert-butyldimethylsilanyloxy)-5-(4-methoxybenzyloxy)-2,4-dimethyloctan-1-ol. TBDMSOTf (0.68 mL, 3 mmol) was added to astirred solution of 29 (1.11 g, 2 mmol) and 2,6-lutidine (0.69 mL, 6mmol) in CH₂Cl₂ (20 mL) at −78° C. The mixture was stirred for 2 h atambient temperature. The reaction was quenched by the addition ofaqueous HCl (0.5 N, 50 mL). The reaction mixture was extracted withCH₂Cl₂, dried over MgSO₄ and the solvent was removed under reducedpressure. Short column chromatography (hexane/EtOAc 4:1) provided thecrude product.

DIBAL (1.0 M in THF, 6 mL, 6 mmol) was added dropwise to a stirredsolution of the TBS-protected aryl ester (1.90 g, 2 mmol) from above inanhydrous CH₂Cl₂ (20 mL) under an atmosphere of N₂ at 0° C. and themixture was stirred for additional 1 h at 0° C. The reaction wasquenched by the careful addition of aqueous sat'd potassium sodiumtartrate (50 mL). The mixture was stirred for 3 h at room temperature.Once the aqueous and organic layers had separated, the aqueous layer wasextracted with CH₂Cl₂ (20 mL). The combined organic layer was washedwith brine and dried over MgSO₄ followed by the evaporation of thesolvent under reduced pressure. The residue was purified by columnchromatography (EtOAc/hexane/EtOAc 3:7) to give pure (997 mg, 1.8 mmol):IR (CHCl₃) 3125, 1544, 1289, 1065 cm⁻¹, ¹H NMR (300 MHz, CDCl₃) δ 7.28(d, 2H, J=8.7 Hz), 6.89 (d, 2H, J=8.7 Hz), 4.51 (d, 1H, J=11.1), 4.41(d, 1H, J=10.8 Hz), 3.83 (d, 3H), 3.79 (m, 1H), 3.64 (m, 4H), 3.36 (m,1H), 2.45 (br s, 1H), 1.93 (m, 2H), 1.63 (m, 4H), 1.00 (d, 2H, J=7.0Hz), 0.92 (s, 24H), 0.14 (s, 6H), 0.13 (s, 6H); ¹³C NMR (75 MHz, CDCl₃)δ 159.1, 130.6, 129.4, 113.6, 80.3, 76.0, 71.2, 65.2, 63.0, 55.1, 39.1,39.0, 29.0, 27.1, 26.1, 25.9, 11.6, −3.6, −3.9, −5.3; LRMS (ESI) 576.8(M+Na).

(2R,3S,4R,5R)-3,8-Bis-(tert-butyldimethylsilanyloxy)-5-(4-methoxybenzyloxy)-2,4-dimethyloctanal (30). Pyridinium sulfurtrioxide (858 mg, 5.4 mmol)was added to a stirred solution of alcohol (997 mg, 1.8 mmol) from aboveand diisopropylethylamine (0.94 mL, 5.4 mmol) in anhydrous CH₂Cl₂ (3.6mL) and DMSO (7.2 mL) at 0° C. The mixture was stirred at ambienttemperature for 1 h. After the reaction was complete, the mixture wasdiluted with ethyl ether (50 mL) and washed with aqueous HCl (0.5N, 50mL) and brine (10 ml). The organic layer was dried over MgSO₄.Filtration and concentration followed by short flash columnchromatography filtration (hexane/EtOAc 4:1) to remove SO₃-pyridineprovided the crude aldehyde 30 as a colorless oil which was used withoutfurther purification: ¹H NMR (300 MHz, CDCl₃) δ 9.69 (s, 1H), 7.22 (d,2H, J=8.6 Hz), 6.85 (d, 2H, J=8.6 Hz), 4.45 (d, 1H, J=11.1 Hz), 4.28 (d,1H, J=11.1 Hz), 3.94 (dd, 1H, J=5.5, 4.0 Hz), 3.79 (s, 3H), 3.60 (t, 2H,J=6.0 Hz), 3.40–3.34 (m, 1H), 2.66–2.58 (m, 1H), 1.92–1.84 (m, 1H),1.67–1.59 (m, 2H), 1.55–1.45 (m, 2H), 1.02 (d, 3H, J=7.0 Hz), 0.98 (d,3H, J=7.0 Hz), 0.89 (s, 9H), 0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 9H).

(1R,2R,3S,4S,5Z)-1-{3-(tert-Butyldimethylsilanyloxy)-1-[3-(tert-butyldimethylsilanyloxy)propyl]-2,4-dimethylocta-5,7-dienyloxymethyl}-4-methoxybenzene(32). CrCl₂ (1.09 g, 9.0 mmol) was added to a stirred solution of thecrude aldehyde (1.8 mmol) from above and 1-bromoallyl trimethylsilane 31(578 mg, 5.4 mmol) in anhydrous THF (18 mL) under an atmosphere of N₂ atroom temperature. The mixture was stirred for 14 h at ambienttemperature, then diluted with ethyl ether followed by filtrationthrough Celite. After the evaporation of the solvent under reducedpressure, the residue was purified by short silica gel columnchromatography (CH₂Cl₂). The resulting residue was used without furtherpurification.

The above product in THF (50 mL) was cooled to 0° C. and Nail (95% w/w,207 mg, 9.0 mmol) was added in one portion. The ice bath was removedafter 15 min and the mixture was stirred for 2 h at ambient temperature.The reaction mixture was cooled to 0° C., quenched with H₂O (10 mL) andextracted with ethyl ether (2×50 mL). The combined organic layer waswashed with brine and dried over MgSO₄ followed by the evaporation ofthe solvent under reduced pressure. The residue was purified by columnchromatography (hexane/EtOAc 4:1) to give pure 32 (622 mg, 1.2 mmol): IR(CHCl₃) 2954, 2931, 2857, 1608, 1513, 1463, 1251, 1098, 1047 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.35 (d, 2H, J=8.6 Hz), 6.96 (d, 2H, J=8.6 Hz),6.41 (ddd, 1H, J=16.7, 11.0, 10.1 Hz), 6.04 (dd, 1H, J=11.1, 11.0 Hz),5.57 (dd, 1H, J=10.1, 16.8 Hz), 5.20 (d, 1H, J=16.7 Hz), 5.06 (d, 1H,J=10.1 Hz), 4.51 (d, 1H, J=11.3 Hz), 4.35 (d, 1H, J=11.3 Hz), 3.81 (s,3H), 3.63–3.57 (m, 3H), 3.28 (dt, 1H, J=5.5, 5.5 Hz), 2.70 (ddq, 1H,J=10.3, 6.9, 3.2 Hz), 1.73–1.58 (m, 3H), 1.50–1.44 (m, 2H), 0.94 (d, 3H,J=6.9 Hz), 0.93–0.91 (m, 21H), 0.06 (s, 6H), 0.05 (s, 6H); ¹³C NMR (75MHz, CDCl₃) 159.1, 134.8, 132.5, 131.0, 129.5, 128.9, 117.1, 113.7,78.9, 76.6, 70.7, 63.2, 55.2, 40.0, 36.4, 31.6, 28.7, 26.2, 26.0, 18.9,18.5, 18.3, 10.9, −3.3, −3.4, −5.3; LRMS (EI) 576, 519, 467, 387, 357,293, 225, 121; HRMS (EI) calcd for C₂₉H₅₁O₄Si₂ 519.3326, found 519.3332;[α]²⁰ _(D) −18.8° (c 0.75, CHCl₃).

(2R)-2-{(4R,5S,6R)-6-[3-(tert-Butyldimethylsilanyloxy)propyl]-2,2,5-trimethyl[1,3]dioxan-4-yl}-propionicacid, 2,6-dimethylphenyl ester (34). A mixture of PMB ether 29 (55.8 mg,0.1 mmol) and palladium (10% Pd/C, 5 mg) in EtOAc (10 mL) was stirred atroom temperature under an H₂ atmosphere (balloon) for 3 h. The mixturewas filtered and concentrated to yield the diol which was used withoutfurther purification. A solution of the crude diol, dimethyl dimethylacetal (12.4 mg, 0.12 mmol) and PPTS (0.1 equiv.) in benzene was stirredfor 5 h at 65° C. The reaction was quenched with aqueous sat'd NaHCO₃(50 mL) followed by washing with water. The aqueous layer was extractedwith ethyl ether (2×50 mL). The combined organic layer was dried overMgSO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by column chromatography (hexane/EtOAc 9:1) toprovide the pure 34 in 52% yield: IR (CHCl₃) 2855, 1742, 1510, 1091cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.03 (br s, 3H), 4.20 (dd, 1H, J=1.7,10.2 Hz), 3.91 (m, 1H), 3.64 (m, 2H), 2.91 (dq, 1H, J=10.2, 6.9 Hz),2.16 (s, 6H), 1.59–1.32 (m, 6H), 1.41 (s, 3H), 1.39 (s, 3H), 1.24 (d,3H, J=4.2 Hz), 0.92 (br s, 12H), 0.06 (s, 6H); ¹³C NMR (75 MHz, CDCl₃)173.7, 148.2, 130.3, 128.5, 125.8, 99.1, 75.2, 73.0, 63.1, 42.3, 31.8,29.9, 29.3, 28.8, 26.0, 19.5, 18.4, 16.4, 12.9, 4.54, −5.19; HRMS (EI)calcd for C₂₇H₄₆O₅Si 478.3115, found 463.2889 (M−CH₃).

(1S,2S,3R,6Z,8S,9S,10S,11Z)-13,9-Bis-(4-methoxybenzyloxy)-14-[(2S,3S,4S,5R,6R)-6-methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl]-2,8,10-trimethyl-1-[(1S,2Z)-1-methylpenta-2,4-dienyl)tetradeca-6,11-dienyloxy]-tert-butyldimethylsilane.NaHMDS (1.0 M in THF, 0.54 mL, 0.54 mmol) was added slowly to a solutionof the salt 33 (475.9 mg, 0.54 mmol) in dry THF (1.08 mL) at 0° C. Themixture was cooled to −78° C. and a solution of the aldehyde 38 (267 mg,0.54 mmol) in THF (0.54 mL×2) was added dropwise. The mixture wasstirred for 20 min at −78° C. and then warmed to room temperature. After4 h at room temperature the mixture was quenched with saturated aqueousNH₄Cl (10 mL) and extracted with CH₂Cl₂ (3×10 mL). The combined organiclayer was dried over anhydrous MgSO₄, evaporated and chromatographed(hexane/EtOAc 9:1) to yield the desired compound (257 mg, 0.28 mmol) asa colorless oil: IR (CHCl₃) 2920, 2861, 2620, 1740, 1520 cm⁻¹, ¹H NMR(300 MHz, CDCl₃) 7.38 (m, 4H), 6.96 (m, 4H), 6.47 (ddd, 1H, J=16.8,11.0, 10.1 Hz), 6.04 (t, 1H, J=11.1 Hz), 5.57 (t, 1H, J=10.5 Hz),5.49–5.12 (m, 6H), 4.75 (d, 2H, J=2.1 Hz), 4.67–4.33 (m, 5H), 4.07 (m,1H), 3.65 (dd, 1H, J=3.3, 6.0 Hz), 3.47 (br s, 7H), 3.35 (dd, 1H, J=4.5,4.7 Hz), 3.27 (t, 1H, J=6.6 Hz), 3.15 (dd, 1H, J=4.5, 6.9 Hz), 2.77 (m,3H), 2.18 (m, 2H), 1.91 (m, 2H), 1.74–1.62 (m, 4H), 1.11–0.99 (m, 18H),0.12 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) 159.2, 159.0, 134.7, 133.7, 132.9,132.5, 131.4, 131.0, 129.6, 129.1, 128.9, 128.6, 117.3, 113.8, 113.7,103.0, 96.5, 88.0, 82.1, 78.8, 74.9, 70.8, 69.7, 55.8, 55.3, 40.0, 39.5,38.3, 35.6, 35.4, 31.3, 30.3, 26.4, 24.2, 23.7, 19.0, 18.8, 18.6, 17.3,15.7, 13.2, 11.0, −3.1, −3.2; LRMS (ESI) 942.5 (M+Na).

Carbamic acid,(1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-bis-(4-methoxybenzyloxy)-14-[(2S,3S,4S,5R,6R)-6-methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl]-2,8,10-trimethyl-1-[(1S,2Z)-1-methylpenta-2,4-dienyl]tetradeca-6,11-dienylester (39). The above compound (128.5 mg, 0.14 mmol) in THF (4 mL) wastreated with TBAF (1.0 M in THF, 0.40 mL, 0.40 mmol) and the mixture wasstirred at room temperature for 48 h. The mixture was diluted with ethylether (30 mL) and washed with water (10 mL). After drying over MgSO₄ andevaporation under vacuum, the resulting alcohol was used without furtherpurification.

A solution of the alcohol in CH₂Cl₂ (8 mL) at 0° C. was treated withtrichloroacetylisocyanate (0.05 mL, 0.42 mmol) and stirred at roomtemperature. After 30 min, the solution was concentrated under reducedpressure and the residue was taken up in MeOH (4 mL). K₂CO₃ (50 mg) wasadded to this solution and the mixture was stirred at room temperaturefor 3 h at room temperature. The mixture was diluted with EtOAc (30 mL).The organic layer was washed with brine. The aqueous layer was extractedwith EtOAc, and the combined extracts were dried over anhydrous Na₂SO₄.Filtration and concentration followed by flash column chromatography(hexane/EtOAc 3:2) provided carbamate 39 (84.9 mg, 72%) as a yellow oil:IR (CHCl₃) 3100, 3019, 2430, 2286, 1720, 1524 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) 7.41 (m, 4H), 7.01 (m, 4H), 6.46 (ddd, 1H, J=16.8, 11.0, 10.1Hz), 6.11 (t, 1H, J=10.8 Hz), 5.62 (t, 1H, J=10.5 Hz), 5.53–5.18 (m,6H), 4.94 (t, 1H, J=6.0 Hz), 4.84 (br s, 2H), 4.81 (d, 2H, J=2.1 Hz),4.71–4.45 (m, 4H), 4.39 (d, 1H, J=5.1 Hz), 4.12 (m, 1H), 3.37 (m, 2H),3.19 (dd, 1H, J=4.5, 6.9 Hz), 2.90 (m, 3H), 2.27 (m, 2H), 1.91 (m, 2H),1.74–1.61 (m, 4H), 1.11–0.99 (m, 18H); ¹³C NMR (75 MHz, CDCl₃) 159.2,159.0, 157.1, 133.7, 133.3, 132.8, 132.2, 131.4, 130.9, 129.8, 129.6,129.1, 128.5, 117.8, 113.8, 113.7, 102.9, 96.5, 88.0, 82.1, 78.4, 78.1,74.9, 70.5, 69.8, 55.8, 55.7, 55.3, 39.5, 38.2, 37.7, 35.8, 35.4, 34.3,30.6, 30.3, 24.2, 23.6, 18.9, 17.8, 17.4, 15.7, 13.2, 9.8; LRMS (ESI)888.4 (M+K).

Carbamic acid,(1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-bis-(4-methoxybenzyloxy)-14-[(2S,3S,4S,5R)-4-methoxymethoxy-3,5-dimethyl-6-oxotetrahydropyran-2-yl]-2,8,10-trimethyl-1-[(1S,2Z)-1-methylpenta-2,4-dienyl]tetradeca-6,11-dienylester. A solution of 39 (42.4 mg, 0.05 mmol) in THF (0.5 mL) and 60%aqueous acetic acid (2.5 mL) was stirred at 70° C. for 4 h. After thereaction was complete by TLC, the mixture was neutralized slowly withsaturated aqueous K₂CO₃ and diluted with EtOAc (20 mL). The aqueousphase was extracted with EtOAc (2×10 mL). The combined organic layerswere dried over MgSO₄ and evaporated under reduced pressure. The crudelactol was used for the next reaction without further purification.

Dess-Martin periodinane reagent (31.8 mg, 0.075 mmol) was added to asolution of the lactol in CH₂Cl₂ (5 mL). The resultant solution wasstirred for 1 h and quenched by the simultaneous addition of saturatedaqueous Na₂S₂O₃ (5 mL) and saturated aqueous NaHCO₃. The aqueous layerwas extracted with CH₂Cl₂ (2×10 mL) and the combined extracts were driedover anhydrous MgSO₄. Filtration and concentration followed by flashcolumn chromatography (hexane/EtOAc 8:2) provided 28.3 mg (68%) of thelactone as a colorless oil: IR (CHCl₃) 2992, 2361, 2332, 1742, 1374,1242, 1047 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) 7.40 (m, 4H), 7.03 (m, 4H),6.51 (ddd, 1H, J=16.8, 11.1, 10.0 Hz), 6.11 (t, 1H, J=11.1 Hz), 5.67 (t,1H, J=10.8 Hz), 5.52–5.18 (m, 7H), 4.94 (t, 1H, J=6.0 Hz), 4.87–4.47 (m,9H), 3.94 (br s, 4H), 3.93 (s, 3H), 3.54 (s, 3H), 3.40 (m, 2H), 3.19(dd, 1H, J=4.5, 6.9 Hz), 2.87 (m, 2H), 2.72 (m, 2H), 2.32–1.89 (m, 7H),1.45 (d, 3H, J=6.6 Hz), 1.15–01.02 (m, 15H); ¹³C NMR (75 MHz, CDCl₃)174.2, 159.2, 159.0, 156.9, 133.6, 133.5, 133.4, 132.2, 131.3, 130.9,129.8, 129.6, 129.5, 129.2, 128.7, 127.8, 113.8, 113.7, 95.4, 88.0,82.7, 79.9, 78.4, 76.5, 75.0, 55.9, 55.7, 55.3, 40.5, 38.6, 37.7, 36.0,35.4, 34.3, 31.3, 30.6, 23.9, 23.6, 23.5, 19.0, 17.8, 14.4, 12.1, 9.8;LRMS (ESI) 872.4 (M+K).

Carbamic acid,(1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-dihydroxy-14-[(2S,3S,4S,5R)-4-hydroxy-3,5-dimethyl-6-oxotetrahydropyran-2-yl]-2,8,10-trimethyl-1-[(1S,2Z)-1-methylpenta-2,4-dienyl]tetradeca-6,11-dienylester (40). A solution of the above lactone (2.83 mg, 0.005 mmol) in THF(2 mL) was treated with aqueous 4N HCl (1 mL). The flask was fitted witha glass stopper and the resulting solution was stirred at roomtemperature for 48 h. Saturated aqueous K₂CO₃ was added dropwisefollowed by EtOAc. The aqueous layer was extracted with EtOAc and thecombined extracts were dried over MgSO₄. Filtration and concentrationfollowed by simple short flash column chromatography (EtOAc/hexane/ether3:2) provided the crude MOM-deprotected compound. A solution of PMBether in CH₂Cl₂ (2 mL) at 0° C. was treated with NaHCO₃ (4.2 mg, 0.5mmol). After 1 h, the mixture was diluted with CH₂Cl₂ and washed withwater. The aqueous layer was extracted with CH₂Cl₂ and the combinedextracts were dried over anhydrous MgSO₄. Filtration and concentrationfollowed by flash column chromatography (EtOAc/hexane 3:2) providedcarbamate 40 (1.1 mg, 0.002 mmol) as a colorless oil: IR (CHCl₃) 2995,2937, 2323, 1755, 1449, 1374, 1242, 1049 cm⁻¹; ¹H NMR (500 MHz, CDCl₃)6.63 (ddd, 1H, J=16.8, 11.0, 10.1 Hz), 6.06 (t, 1H, J=11.0 Hz),5.46–5.32 (m, 5H), 5.25 (d, 1H, J=17 Hz), 5.14 (d, 1H, J=10.0 Hz), 4.94(t, 1H, J=6.0 Hz), 4.74 9m, 1H), 4.60 (br s, 1H), 4.54 (m, 1H), 3.65 (m,1H), 3.38 (d, 1H, J=5.0 Hz), 3.27 (t, 1H, J=6.0 Hz), 3.00 (m, 1H), 2.78(m, 1H), 2.63 (m, 2H), 2.18 (m, 1H), 2.01 (m, 1H), 1.83 (m, 1H), 1.77(m, 1H), 1.35 (d, 3H, J=7.0), 1.01–0.93 (m, 15H); ¹³C NMR (125 MHz,CDCl₃) 174.2, 157.3, 133.6, 132.9, 129.6, 128.9, 125.0, 121.4, 118.0,95.5, 82.6, 79.7, 79.2, 72.8, 55.9, 40.5, 39.9, 38.6, 35.4, 34.7, 31.6,23.8, 19.2, 18.2, 17.7, 15.7, 14.8, 12.0; LRMS (ESI) 571.4 (M+Ka); HRMS(ESI) calcd for C₃₁H₅₁NO₇Na 588.3303, found 588.3336 (M+K); [α]²⁰ _(D)+34.0 (c 0.05, CHCl₃).

Carbamic acid,(1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-dihydroxy-14-[(2S,3S,4S,5R)-4-methoxymethoxy-3,5-dimethyl-6-oxotetrahydropyran-2-yl]-2,8,10-trimethyl-1-[(1S,2Z)-1-methylpenta-2,4-dienyl]tetradeca-6,11-dienylester (41). Carbamate 39 (8.49 mg, 0.01 mmol) was subjected to thelactonization procedure described above. The removal of the PMBprotecting group was accomplished by treating with NaHCO₃ and DDQ. Flashchromatography (EtOAc/hexane 3:2) provided 41 (2.9 mg, 49% overall 3steps) as a colorless oil: IR (CHCl₃) 3404, 2362, 1749, 1373, 1241, 1049cm⁻¹; ¹H NMR (500 MHz, CDCl₃) 6.62 (ddd, 1H, J=16.8, 11.0, 10.1 Hz),6.04 (t, 1H, J=11.0 Hz), 5.48–5.33 (m, 5H), 5.24 (d, 1H, J=17 Hz), 5.13(d, 1H, J=10.0 Hz), 4.77–4.60 (br m, 5H), 4.48 (m, 1H), 3.65 (m, 1H),3.41 (s, 3H), 3.28 (d, 1H, J=7.0 Hz), 3.23 (t, 1H, J=5.5 Hz), 3.02 (m,1H), 2.62 (m, 2H), 2.25–2.18 (m, 3H), 2.04 (m, 2H), 1.90 (m, 1H), 1.88(m, 1H), 1.83 (m, 1H), 1.77–1.67 (m, 2H), 1.51 (m, 2H), 1.34 (d, 3H,J=7.0), 1.02–0.92 (m, 15H); ¹³C NMR (125 MHz, CDCl₃) 174.1, 157.3,133.6, 132.9, 132.2, 129.6, 128.9, 125.0, 121.4, 118.0, 95.5, 82.6,79.7, 79.2, 72.8, 55.9, 40.5, 39.8, 38.6, 35.4, 34.9, 34.7, 31.6, 23.8,19.2, 18.2, 17.2, 15.7, 14.8, 12.0; LRMS (ESI) 616.3 (M+Na); HRMS (ESI)calcd for C₃₃H₅₅NO₈Na 616.3825, found 616.3829 (M+Na); [α]²⁰ _(D) +59.0(c 0.1, CHCl₃).

Carbamic acid,(1S,2S,3R,6Z,8S,9S,10S,11Z)-3,9-dihydroxy-14-[(2S,3S,4S,5R,6R)-6-methoxy-4-methoxymethoxy-3,5-dimethyltetrahydropyran-2-yl]-2,8,10-trimethyl-1-[(1S,2Z)-1-methylpenta-2,4-dienyl]tetradeca-6,11-dienylester (42). Carbamate 39 (4.25 mg, 0.005 mmol) was subjected to thedeprotection procedure of PMB described in the preparation of 40. Flashchromatography (EtOAc/hexane 3:2) of the crude product provided 42 (2.8mg, 92%) as a colorless oil: IR (CHCl₃) 3115, 2749, 2328, 1676, 1508,1215 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) 6.76 (ddd, 1H, J=16.8, 11.0, 10.1Hz), 6.18 (t, 1H, J=10.8 Hz), 5.70–5.46 (m, 5H), 5.35 (d, 1H, J=16.8Hz), 4.49 (dd, J=4.5, 6.6 Hz), 4.82 (d, 2H, J=2.4 Hz), 4.73 (br s, 2H),4.43 (d, 1H, J=5.1 Hz), 4.15, (m, 1H), 3.78 (m, 1H), 3.56 (s, 3H), 3.54(s, 3H), 3.36 (t, 2H, J=6.9 Hz), 3.14 (m, 1H), 2.76 (m, 2H), 2.35–2.18(m, 6H), 2.00–1.60 (m, 7H), 1.22 (d, 3H, J=7.2 Hz), 1.16–1.12 (m, 12H),1.07 (d, 3H, J=7.2 Hz); ¹³C NMR (125 MHz, CDCl₃) 157.3, 133.7, 133.5,132.2, 132.0, 130.0, 128.7, 118.0, 109.6, 103.0, 96.5, 82.1, 79.7, 79.1,72.7, 55.8, 39.9, 39.5, 38.3, 35.5, 35.0, 34.8, 34.6, 30.2, 29.8, 24.3,18.1, 17.7, 15.7, 15.4, 14.2, 13.2, 8.1; LRMS (ESI) 632.4 (M+Na); HRMS(ESI) calcd for C₃₃H₅₅NO₈Na 632.4138, found 632.4139; [α]²⁰ _(D) +21.6(c 0.25, CHCl₃).

(12S,13S,14S,19R,20R,21R,22S)-21-(tert-Butyldimethylsilanyloxy)-13,19-bis-(4-methoxybenzyloxy)-12,14,20,22-tetramethylhexacosa-10,15,23,25-tetraen-1-(tert-Butyldimethylsilanyl)-ol(45). NaHMDS (1.0 M in THF, 0.45 mL, 0.45 mmol) was slowly added to asolution of the salt 21 (322 mg, 1.1 mmol) in dry THF (0.3 mL) at 0° C.The resulting red solution was stirred at room temperature for 20 min.The mixture was cooled to −78° C. and a solution of the aldehyde 44 (120mg, 0.42 mmol) in THF (0.1 mL×2) was added dropwise. The mixture wasstirred for 20 min at −78° C. and then warmed to room temperature. After4 h, the mixture was quenched with saturated NH₄Cl (5 mL) and extractedwith ethyl ether (3×10 mL). The combined organic layers were dried overanhydrous MgSO₄, evaporated and the residue was column chromatographed(hexane/ether 9:1) to yield 163 mg (75%) as a colorless oil: IR (CHCl₃)2928, 2854, 1617, 1517, 1462, 1390, 1249, 1114, 1035, 833, 726 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.44–7.38 (m, 2H), 6.90–6.85 (m, 2H), 5.42 (s,1H), 5.39 (ddd, J=11.7, 10.2, 7.2 Hz, 1H), 5.24 (apparent t, J=10.2 Hz,1H), 4.08–4.00 (m, 2H), 3.79 (s, 3H), 3.61 (t, J=6.5 Hz, 2H), 3.54 (dd,J=10.5, 1.9 Hz, 1H), 2.69 (dd, J=16.1, 9.2 Hz, 1H), 2.04 (apparent d,J=6.6 Hz, 2H), 1.71–1.68 (m, 1H), 1.54–1.50 (m, 3H), 1.27 (br, 1H), 1.20(d, J=6.9 Hz, 3H), 0.91 (s, 9H), 0.06 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ160.0, 133.3, 132.6, 132.5, 132.1, 130.7, 128.9, 128.7, 127.6, 113.7,101.8, 83.9, 74.2, 63.6, 55.5, 33.9, 33.3, 30.4, 30.1, 30.0, 29.9, 29.8,29.7, 28.0, 26.3, 26.2, 18.7, 16.3, 11.5, −4.9; LRMS (API-ES) 541(M+Na)⁺, 493, 431, 365, 295, 251; [α]²⁰ _(D) +26.0 (c 0.90, CHCl₃).

To a solution of 164 mg (0.32 mmol) of the above acetal in dry CH₂Cl₂(2.0 mL) DIBAL (1.0 M in hexane, 0.95 mL, 0.96 mmol) at 0° C. was addeddropwise. After 2 h, the mixture was quenched with saturated sodiumpotassium tartrate solution (20 mL) followed by vigorously stirring for4 h. The aqueous phase was extracted with CH₂Cl₂ (3×10 mL) and thecombined organic layers were washed with brine (10 mL). After dryingover MgSO₄ and evaporation under vacuum, flash column chromatography(hexane/ether 9:1) provided 115 mg (70%) of alcohol as a colorless oil:IR (CHCl₃) 3430, 2928, 2855, 1613, 1514, 1463, 1249, 1098, 1038, 835,776 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.28–7.25 (m, 2H), 6.88–6.85 (m,2H), 4.59 (d, J=10.8 Hz, 1H), 4.47 (d, J=10.8 Hz, 1H), 3.80 (s, 3H),3.65–3.50 (m, 4H), 3.36 (dd, J=5.9, 3.9 Hz, 1H), 2.86–2.78 (m, 1H),2.11–2.01 (m, 2H), 1.98–1.95 (m, 1H), 1.77 (br, 1H), 1.50 (br, 3H), 1.27(br, 1H), 0.97 (apparent t, J=7.1 Hz, 6H), 0.90 (s, 9H), 0.05 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ 159.2, 132.8, 131.1, 130.0, 129.5, 113.8,84.5, 73.7, 66.4, 63.5, 55.3, 37.6, 34.6, 33.0, 29.8, 29.7, 29.64,29.61, 29.5, 27.7, 26.1, 25.9, 18.8, 18.4, 11.7, −5.1; LRMS (EI) 541(M+Na)⁺, 462, 375, 325, 255, 207, 122; HRMS (EI) calcd for C₂₇H₄₇O₄Si₁463.3254 (M−^(t)Bu)⁺, found 463.3254; [α]²⁰ _(D) +25.9 (c 0.48, CHCl₃).

The above alcohol (94 mg, 0.18 mmol) in CH₂Cl₂ (2 mL) was treated withDess-Martin periodinane (120 mg, 0.27 mmol). After 2 h, the mixture wasquenched with saturated NaHCO₃ (20 mL). The aqueous layer was extractedwith ethyl ether (10 mL×2) and the combined extracts were dried overanhydrous MgSO₄. Filtration and concentration followed by short flashcolumn chromatography (hexane/EtOAc 9:1) to remove the residue fromDess-Martin reagent provided 78 mg (83%) of the crude aldehyde as acolorless oil which was used for the next reaction without furtherpurification. NaHMDS (1.0 M in THF, 0.15 mL, 0.15 mmol) was slowly addedto a solution of the salt 33 (140 mg, 0.17 mmol) in dry THF (0.15 mL) at0° C. The resulting red solution was stirred at room temperature for 20min. The mixture was cooled to −78° C. and a solution of the aldehydeabove (69 mg, 0.13 mmol) in THF (0.05 mL×2) was added dropwise. Themixture was stirred for 20 min at −78° C. and then warmed to roomtemperature. After 4 h at room temperature, the mixture was quenchedwith saturated NH₄Cl (2 mL) and extracted with ethyl ether (3×5 mL). Thecombined organic layers were dried over anhydrous MgSO₄, evaporated andthe residue was purified by column chromatography (hexane/ether 9:1) toyield 45 (111 mg, 65% for 2 steps) as a colorless oil: IR (CHCl₃) 2926,1612, 1513, 1462, 1361, 1250, 1173, 1098, 836, 774 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 7.40–7.33 (m, 4H), 6.99–6.93 (m, 4H), 6.49 (ddd, J=16.8,10.8, 10.7 Hz, 1H), 6.06 (apparent t, J=11.0 Hz, 1H), 5.59 (d, J=10.5Hz, 1H), 5.51 (d, J=9.8 Hz, 1H), 5.44–5.31 (m, 3H), 5.23 (d, J=16.8 Hz,1H), 5.13 (d, J=10.1 Hz, 1H), 4.68–4.57 (m, 3H), 4.42 (d, J=11.3 Hz,1H), 3.90 (s, 6H), 3.69 (t, J=6.5 Hz, 2H), 3.37–3.36 (m, 1H), 3.14 (q,J=3.7 Hz, 1H), 2.82–2.71 (m, 2H), 2.08–2.00 (m, 4H), 1.78–1.77 (m, 2H),1.71–1.58 (m, 6H), 1.36 (br, 11H), 1.11 (d, J=6.7 Hz, 6H), 1.04–1.00 (m,24H), 0.15 (s, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 159.3, 159.1, 134.8,133.8, 132.5, 132.0, 131.5, 131.1, 129.9, 129.7, 129.2, 129.1, 128.6,117.3, 113.8, 113.7, 88.1, 79.1, 74.8, 71.0, 63.4, 55.4, 40.1, 36.6,35.8, 35.3, 33.0, 31.5, 30.0, 29.8, 29.7, 29.6, 27.7, 26.4, 26.1, 23.8,19.0, 18.9, 18.5, 17.6, 11.1, −3.2, −3.3, −5.1; LRMS (EI)890(M−^(t)Bu)⁺, 866; HRMS (EI) calcd for C₅₄H₈₉O₆Si₂865.5258(M−^(t)Bu)⁺, found 865.5225; [α]²⁰ _(D) +20.5 (c 0.60, CHCl₃).

(12S,13S,14S,19R,20R,21R,22S)-21-(tert-Butyldimethylsilanyloxy)-13,19-bis-(4-methoxybenzyloxy)-12,14,20,22-tetramethylhexacosa-10,15,23,25-tetraenoicacid (46). To a solution of TBS ether 45 (93 mg, 0.098 mmol) in THF (2ml) was slowly added HF-pyridine in pyridine (4 ml, prepared by slowaddition of 1.2 ml pyridine to 0.3 ml HF-pyridine complex followed bydilution with 3 ml THF). The mixture was stirred overnight at roomtemperature and quenched with sat'd NaHCO₃ (20 ml). The aqueous layerwas separated and extracted with CH₂Cl₂ (3×10 ml). The combined organiclayer was washed with sat'd CuSO₄ (3×20 ml), dried over MgSO₄, andconcentrated. Flash column chromatography (EtOAc/Hexane 1:4) afforded 64mg (78%) of the alcohol: IR (CHCl₃) 3429, 2928, 2855, 1694, 1612, 1513,1462, 1250, 1173, 1038, 836, 773 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.40–7.33 (m, 4H), 6.99–6.95 (m, 4H), 6.49 (ddd, J=16.8, 10.6, 10.5 Hz,1H), 6.05 (apparent t, J=11.0 Hz, 1H), 5.58 (d, J=10.9 Hz, 1H), 5.52 (d,J=9.7 Hz, 1H), 5.46–5.34 (m, 2H), 5.23 (d, J=16.8 Hz, 1H), 5.14 (d,J=10.1 Hz, 1H), 4.68–4.57 (m, 3H), 4.45–4.41 (m, 1H), 3.89 (s, 3H), 3.88(s, 3H), 3.72–3.67 (m, 2H), 3.37–3.36 (m, 2H), 3.14 (q, J=3.6 Hz, 1H),2.80–2.70 (m, 2H), 2.08–1.99 (m, 4H), 1.78–1.77 (m, 2H), 1.71–1.58 (m,6H), 1.36 (br, 1H), 1.10 (d, J=6.6 Hz, 6H), 1.02 (d, J=2.6 Hz, 6H), 1.00(s, 9H), 0.15 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 159.3, 159.1, 134.8,134.8, 133.8, 132.5, 132.1, 131.5, 131.1, 129.9, 129.7, 129.2, 129.1,128.6, 117.3, 113.8, 113.7, 88.1, 79.0, 76.7, 74.8, 71.0, 63.1, 55.4,40.1, 36.6, 35.8, 35.4, 32.9, 31.4, 30.0, 29.7, 29.63, 29.56, 27.6,26.4, 25.9, 23.8, 19.0, 18.9, 18.6, 17.6, 11.1, −3.2, −3.3; LRMS(API-ES) 871 (M+K)⁺, 445, 364, 338; [α]²⁰ _(D) +27.0 (c 0.24, CHCl₃).

The above alcohol (0.213 g, 0.26 mmol) in CH₂Cl₂ (10 mL) was treatedwith Dess-Martin periodinane (160 mg, 0.38 mmol). After 2 h, the mixturewas quenched with saturated NaHCO₃ (10 mL). The aqueous layer wasextracted with ethyl ether (10 mL×2) and the combined extracts weredried over anhydrous MgSO₄. Filtration and concentration followed byshort flash column chromatography (hexane/EtOAc 8:2) to remove theresidue from Dess-Martin reagent provided the aldehyde as a colorlessoil which was used for the next reaction without further purification. Asolution of the above aldehyde in 1 ml of THF and 0.5 ml of H₂O wastreated with 0.74 ml (1.48 mmol) of a 2M solution of 2-methyl-2-butenein THF, 0.11 g (0.77 mmol) of NaH₂PO₄.H₂O and 0.087 g (0.77 mmol) ofNaClO₂. The reaction mixture was stirred for 2 h, diluted with 20 ml of1N HCl and extracted with CH₂Cl₂ (2×20 ml). The combined organic layerswere dried over MgSO₄, concentrated in vacuo and the residue waschromatographed on SiO₂ (EtOAc/hexane 1:3) to yield 192 mg (89% for 2steps) of the acid 46 as a viscous oil: IR (CHCl₃) 3398, 2929, 2855,1710, 1612, 1513, 1249, 1040 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.46–7.40(m, 4H), 7.05–6.99 (m, 4H), 6.55 (ddd, J=16.8, 10.6, 10.3 Hz, 1H), 6.12(apparent t, J=11.0 Hz, 1H), 5.66 (d; J=10.6 Hz, 1H), 5.58 (d, J=11.0Hz, 1H), 5.52–5.37 (m, 3H), 5.30 (d, J=16.8 Hz, 1H), 5.21 (d, J=10.0 Hz,1H), 4.74–4.64 (m, 3H), 4.52–4.48 (m, 1H), 3.95 (s, 6H), 3.72 (dd,J=6.2, 3.3 Hz, 1H), 3.43 (dd, J=10.5, 5.9 Hz, 1H), 3.21 (q, J=3.8 Hz,1H), 2.87–2.77 (m, 3H), 2.49 (t, J=7.4 Hz, 2H), 2.15–2.09 (m, 4H),1.87–1.70 (m, 5H), 1.43 (br, 1H), 1.17 (d, J=6.8 Hz, 6H), 1.10 (d, J=3.0Hz, 6H), 1.07 (s, 9H), 0.22 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 180.06159.3, 159.1, 134.8, 133.8, 132.5, 132.1, 131.5, 131.1, 129.8, 129.7,129.2, 129.1, 128.6, 117.3, 113.8, 113.7, 88.1, 79.0, 76.7, 74.8, 70.9,55.4, 40.1, 36.6, 35.8, 35.4, 34.2, 31.4, 29.9, 29.5, 29.3, 29.2, 27.6,26.4, 24.8, 23.8, 19.0, 18.9, 18.6, 17.6, 11.1, −3.2, −3.3; LRMS(API-ES) 846 (M)⁻, 845 (M−H)⁻; [α]²⁰ _(D) +24.5 (c 0.38, CHCl₃).

(1S,13S,14S,15S,20R,21R,22R)-14,20-Dihydroxy-13,15,21-trimethyl-22-(1-methylpenta-2,4-dienyl)-oxacyclodocosa-11,16-dien-2-one(43). To 46 (146 mg, 0.17 mmol) in THF (2 mL) was added TBAF (1.0 M inTHF, 1.72 mL, 1.72 mmol) and the mixture was stirred at room temperaturefor 48 h. The reaction mixture was diluted with ethyl ether (30 mL) andwas washed with water (10 mL). After drying over MgSO₄ and evaporationunder vacuum, the crude was chromatographed on SiO₂ (EtOAc/hexane 1:4)to yield 72 mg (57%) of the acid as a colorless oil: IR (CHCl₃) 3467,2927, 2854, 1710, 1612, 1513, 1460, 1248, 1174, 1036 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 7.39–7.32 (m, 4H), 6.98–6.93 (m, 4H), 6.69 (ddd, J=16.7,10.7, 10.6 Hz, 1H), 6.18 (apparent t, J=10.9 Hz, 1H), 5.57 (d, J=10.4Hz, 1H), 5.50 (d, J=10.9 Hz, 1H), 5.46–5.37 (m, 3H), 5.30 (d, J=17.2 Hz,1H), 5.19 (d, J=10.1 Hz, 1H), 4.69–4.58 (m, 3H), 4.47–4.44 (m, 1H), 3.89(s, 3H), 3.87 (s, 3H), 3.58–3.56 (m, 2H), 3.16 (q, J=3.5 Hz, 1H),2.86–2.79 (m, 2H), 2.73–2.70 (m, 1H), 2.42 (t, J=7.3 Hz, 2H), 2.14–2.02(m, 4H), 1.91–1.89 (m, 1H), 1.81–1.71 (m, 4H), 1.37 (br, 1H), 1.12 (d,J=6.6 Hz, 6H), 1.07 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 179.6 159.3, 159.1, 135.6, 134.1, 132.4, 132.0, 131.4,130.4, 130.1, 129.9, 129.6, 129.3, 128.3, 117.9, 113.9, 113.8, 88.1,83.0, 78.2, 74.9, 71.0, 55.4, 36.7, 36.2, 36.1, 35.4, 34.1, 30.6, 29.9,29.8, 29.5, 29.3, 29.2, 27.6, 24.8, 23.7, 19.0, 17.7, 17.5, 6.9; LRMS(API-ES) 755.5 (M+Na)⁺, 866; [α]²⁰ _(D) +31.3 (c 0.64, CHCl₃).

A solution of above hydroxy acid (60 mg, 0.081 mmol) in THF (1 ml) wastreated at 0° C. with Et₃N (0.068 ml, 0.49 mmol) and2,4,6-trichlorobenzoyl chloride (0.064 ml, 0.41 mmol). The reactionmixture was stirred at 0° C. for 30 min and then added to a 4-DMAP (41ml, 0.81 mmol, 0.02 M solution in toluene) at 25° C. and stirred forovernight. The reaction mixture was concentrated, EtOAc (10 mL) wasadded and the crude was washed with 1N HCl (2×10 ml), dried over MgSO₄.Purification by flash column chromatography (EtOAc/hexane 1:9) furnishedmacrolactone (33 mg, 57%) as a colorless oil: IR (CHCl₃) 2926, 2855,1730, 1612, 1513, 1459, 1248, 1174, 1109 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.41–7.35 (m, 4H), 6.98–6.94 (m, 4H), 6.55 (ddd, J=16.5, 10.9, 10.6 Hz,1H), 6.06 (apparent t, J=10.8 Hz, 1H), 5.66 (apparent t, J=10.0 Hz, 1H),5.48–5.29 (m, 4H), 5.24 (d, J=6.9 Hz, 1H), 5.16 (d, J=10.3 Hz, 1H), 5.01(dd, J=7.5, 3.5 Hz, 1H), 4.66–4.53 (m, 3H), 4.43 (d, J=10.6 Hz, 1H),3.89 (s, 3H), 3.85 (s, 3H), 3.20–3.18 (m, 1H), 3.13 (d, J=9.6 Hz, 1H),2.97–2.89 (m, 1H), 2.76–2.64 (m, 2H), 2.37–2.19 (m, 3H), 2.04–1.98 (m,4H), 1.78–1.57 (m, 4H), 1.38 (br, 1H), 1.16–1.10 (m, 9H), 0.99 (d, J=6.6Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.4 159.6, 159.3, 134.4, 133.7,132.5, 131.8, 131.4, 131.0, 130.2, 130.0, 129.9, 129.4, 129.3, 118.0,114.2, 114.0, 89.0, 80.6, 76.6, 75.7, 72.0, 55.6, 38.3, 37.5, 36.1,34.9, 34.7, 31.7, 30.0, 29.6, 29.0, 28.8, 28.7, 27.2, 25.1, 24.5, 20.0,18.8, 17.4, 10.4; HRMS (EI) calcd for C₄₆H₆₆O₆ 714.4859, found 714.4848;[α]²⁰ _(D) +5.8 (c 0.39, CHCl₃).

The above macrolactone (12 mg, 16. μmol) was dissolved in CH₂Cl₂ (2ml)—H₂O (0.2 ml) and DDQ (12 mg, 53 μmol) was added at 0° C. After 1 hof stirring at 0° C., the reaction mixture was quenched by adding sat'dNaHCO₃ (5 ml). The organic phase was washed by sat'd NaHCO₃ solution(3×20 ml) and brine, dried over MgSO₄ and concentrated. Purification byflash column chromatography (EtOAc/hexane 1:4) furnished macrolactone(6.8 mg, 85%) as a colorless oil: IR (CHCl₃) 3434, 2926, 2854, 2359,2341, 1731, 1651, 1505, 1456, 1377, 1261, 1107, 965, 905, 803 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 6.75 (dt, J=16.8, 10.9 Hz, 1H), 6.13 (t, J=10.9Hz, 1H), 5.60–5.56 (m, 1H), 5.54–5.46 (m, 2H), 5.42–5.30 (m, 3H), 5.25(d, J=10.1 Hz, 1H), 5.08 (dd, J=8.9, 2.6 Hz, 1H), 3.49 (ddd, J=9.5, 7.4,2.8 Hz, 1H), 3.37 (dd, J=7.3, 4.3 Hz, 1H), 3.18–3.05 (m, 1H), 2.86–2.74(m, 2H), 2.43–2.30 (m, 3H), 2.23–2.05 (m, 2H), 1.84 (br, 9H), 1.42 (br,9H), 1.23 (d, J=6.8 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 1.17 (d, J=6.9 Hz,3H), 1.11 (d, J=6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.4, 134.6,132.4, 131.9, 130.5, 129.9, 129.8, 129.1, 117.9, 80.1, 76.4, 72.9, 40.0,36.9, 35.4, 34.8, 34.6, 34.5, 29.0, 28.6, 28.4, 28.3, 28.1, 26.9, 24.8,24.2, 18.9, 18.8, 17.1, 9.6; HRMS (EI) calcd for C₃₀H₄₉O₃ 456.3603(M−OH)⁺, found 456.3622; [α]²⁰ _(D) +29.0 (c 0.10, CHCl₃).

(12S,13S,14S,19R,20R,21R,22S)-12,14,20,22-Tetramethylhexacosa-10,15,23,25-tetraene-1,13,19,21-tetraol(47). The protected alcohol 45 (54 mg, 57 μmol) was dissolved in CH₂Cl₂(3 ml)—H₂O (0.3 ml) and DDQ (39 mg, 0.17 mmol) was added at 0° C. After1 h of stirring at 0° C., the reaction mixture was quenched by addingsat'd NaHCO₃ (10 ml). The organic phase was washed by sat'd NaHCO₃solution (3×20 ml) and brine, dried over MgSO₄ and concentrated.Purification by flash column chromatography (EtOAc/hexane 1:9) furnishedthe diol (20 mg, 53%) as a colorless oil: IR (CHCl₃) 3434, 2958, 2924,2853, 2362, 1463, 1382, 1246, 1095, 1021, 832, 773 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 6.58 (ddd, J=16.7, 10.7, 10.6 Hz, 1H), 6.05 (apparent t,J=11.0 Hz, 1H), 5.62 (t, J=10.3 Hz, 1H), 5.55–5.45 (m, 1H), 5.41–5.27(m, 3H), 5.21 (d, J=7.6 Hz, 1H), 5.14 (d, J=10.2 Hz, 1H), 3.74–3.72 (m,1H), 3.65–3.63 (m, 1H), 3.60 (t, J=6.6 Hz, 2H), 3.20 (dd, J=6.1, 5.4 Hz,1H), 2.96–2.91 (m, 1H), 2.69–2.56 (m, 2H), 2.17–1.95 (m, 4H), 1.60–1.51(m, 8H), 1.27 (br, 111H), 1.03 (d, J=7.0 Hz, 3H), 0.98 (d, J=6.7 Hz,3H), 0.97 (d, J=6.7 Hz, 3H), 0.92 (s, 11H), 0.90 (s, 10H), 0.10 (s, 3H),0.08 (s, 3H), 0.06 (s, 6H); LRMS (API-ES) 729.5 (M+Na)⁺, 557.5, 413,243; [α]²⁰ _(D) +48.0 (c 0.025, CHCl₃).

To an above solution (20 mg, 28 μmol) in THF (1 mL) was added TBAF (1.0M in THF, 0.28 mL, 0.28 mmol) and the mixture was stirred at roomtemperature for 2 h. The reaction mixture was diluted with EtOAc (10 mL)and was washed with water (10 mL). After drying over MgSO₄ andevaporation under vacuum, the crude was chromatographed on SiO₂(EtOAc/hexane 1:3) to yield 11 mg (83%) of the alcohol 47 as a colorlessoil: IR (CHCl₃) 3378, 2925, 2853, 2359, 1651, 1455, 1377, 1056, 971, 903cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

{tilde over (□)}□□. ddd, J=16.8, 10.6, 10.5 Hz, 1H), 6.21 (apparent t,J=11.0 Hz, 1H), 5.54–5.46 (m, 1H), 5.43–5.36 (m, 2H), 5.31–5.18 (m, 4H),3.84 (dd, J=7.3, 4.6 Hz, 1H), 3.65 (apparent t, J=6.6 Hz, 2H), 3.46 (d,J=9.3 Hz, 1H), 3.22 (t, J=5.6 Hz, 1H), 2.86–2.78 (m, 1H), 2.72–2.59 (m,2H), 2.23–2.02 (m, 4H), 1.71–1.53 (m, 8H), 1.29–1.26 (m, 13H), 1.01–0.91(m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 134.5, 133.8, 132.2, 132.1, 131.9,131.3, 128.9, 119.1, 80.6, 79.1, 76.1, 63.2, 53.6, 37.6, 36.4, 35.5,35.1, 34.5, 32.9, 29.8, 29.6, 29.5, 29.4, 27.7, 25.8, 24.2, 18.1, 16.7,15.3, 4.5; LRMS (API-ES) 517 (M+K)⁺, 501 (M+Na)⁺, 479 (M+H)⁺, 461(M+H-H₂O)⁺, 443; [α]²⁰ _(D) +43.3 (c 0.18, CHCl₃).

(12S,13S,14S,19R,20R,21R,22S)-13,19,21-Trihydroxy-12,14,20,22-tetramethylhexacosa-10,15,23,25-tetraenoicacid methyl ester (48). To an acid 46 (34 mg, 40 μmol) in DMF (3 ml)K₂CO₃ (0.017 g, 0.12 mmol) and MeI (0.009 ml, 0.06 mmol) were added andstirred for 1 h at room temperature. The reaction mixture was quenchedby H₂O (1 ml) and extracted with EtOAc (3×5 ml) and washed with brine (5ml). The organic phase was dried over MgSO₄ and evaporated and theresidue was used as crude without no further purification (36 mg, 85%):IR (CHCl₃) 2928, 2855, 1740, 1613, 1513, 1462, 1301, 1248, 1172, 1038,836, 773 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.30–7.24 (m, 4H), 6.90–6.86(m, 4H), 6.39 (ddd, J=16.9, 10.7, 10.6 Hz, 1H), 5.96 (apparent t, J=11.0Hz, 1H), 5.50 (d, J=10.3 Hz, 1H), 5.42 (d, J=10.7 Hz, 1H), 5.36–5.21 (m,3H), 5.14 (d, J=16.8 Hz, 1H), 5.04 (d, J=9.9 Hz, 1H), 4.59–4.47 (m, 3H),4.39–4.31 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.67 (s, 3H), 3.57 (dd,J=5.9, 3.3 Hz, 1H), 3.28–3.26 (m, 1H), 3.05 (q, J=3.7 Hz, 1H), 2.71–2.61(m, 3H), 2.30 (t, J=7.5 Hz, 2H), 1.99–1.90 (m, 4H), 1.68–1.59 (m, 5H),1.26 (br, 11H), 1.01 (d, J=6.6 Hz, 6H), 0.91 (br, 15H), 0.05 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ 177.4, 159.3, 159.1, 134.8, 133.8, 132.5,132.1, 131.5, 131.1, 129.8, 129.7, 129.2, 129.1, 128.6, 117.3, 113.8,113.7, 88.1, 79.0, 55.4, 51.6, 40.0, 36.5, 35.8, 35.4, 34.2, 31.4, 29.9,29.8, 29.5, 29.4, 29.3, 27.6, 26.4, 25.1, 23.7, 19.0, 18.6, 17.6, 11.1,−3.2, −3.3; LRMS (API-ES) 883.6 (M+Na)⁺; [α]²⁰ _(D) +24.7 (c 1.6,CHCl₃).

The above ester (41 mg, 47 μmol) was dissolved in CH₂Cl₂ (2 ml)—H₂O (0.4ml) and DDQ (32 mg, 0.14 mmol) was added at 0° C. and was followed sameprocedure for 43. Purification by flash column chromatography(EtOAc/Hexane 1:8) furnished the diol (25 mg, 84%) as a colorless oil:IR (CHCl₃) 3487, 2924, 2850, 1741, 1602, 1463, 1367, 1249, 838, 761cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.59 (ddd, J=16.8, 10.8, 10.6 Hz, 1H),6.04 (apparent t, J=11.0 Hz, 1H), 5.62 (t, J=10.1 Hz, 1H), 5.54–5.46 (m,1H), 5.41–5.30 (m, 3H), 5.23 (d, J=17.9 Hz, 1H), 5.14 (d, J=10.2 Hz,1H), 3.75–3.71 (m, 1H), 3.68 (s, 3H), 3.65–3.63 (m, 1H), 3.20 (t, J=5.8Hz, 1H), 2.96–2.90 (m, 1H), 2.69–2.58 (m, 2H), 2.31 (t, J=7.6 Hz, 2H),2.17–1.95 (m, 5H), 1.62–1.52 (m, 5H), 1.29 (br, 11H), 1.03 (d, J=6.9 Hz,3H), 0.98 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 0.93 (s, 12H), 0.10(s, 3H), 0.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) 6174.3, 134.4, 133.7,132.0, 131.4, 129.4, 128.8, 118.1, 114.3, 79.0, 78.7, 71.2, 51.4, 42.5,35.8, 35.7, 35.5, 34.4, 34.1, 29.7, 29.3, 29.2, 29.1, 27.6, 26.1, 24.9,24.3, 19.2, 18.3, 17.9, 15.0, 14.1, 9.5, −3.7, −3.9; LRMS (API-ES) 643.5(M+Na)⁺, 471.4; [α]²⁰ _(D) +41.6 (c 0.74, CHCl₃).

To an above solution (25 mg, 40 μmol) in THF (2 mL) was added TBAF (1.0M in THF, 0.12 mL, 0.12 mmol) and the mixture was stirred at roomtemperature for 2 h. The reaction mixture was diluted with EtOAc (10 mL)and was washed with water (10 mL). After drying over MgSO₄ andevaporation under vacuum, the crude was chromatographed on SiO₂(EtOAc/hexane 1:3) to yield 8.5 mg (93%) of the ester 48 as a colorlessoil: IR (CHCl₃) 3444, 2952, 2925, 2847, 1734, 1451, 1379, 1237, 1197,1451, 967 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

{tilde over (□)}□□. ddd, J=16.8, 10.7, 10.6 Hz, 1H), 6.20 (apparent t,J=10.7 Hz, 1H), 5.54–5.46 (m, 1H), 5.43–5.36 (m, 2H), 5.31–5.18 (m, 4H),3.83 (dd, J=9.0, 3.9 Hz, 1H), 3.67 (s, 3H), 3.46 (dd, J=9.3, 2.0 Hz,1H), 3.22 (apparent t, J=5.4 Hz, 1H), 2.85–2.78 (m, 1H), 2.72–2.59 (m,2H), 2.31 (t, J=7.4 Hz, 3H), 2.20–1.95 (m, 3H), 1.74–1.59 (m, 6H), 1.29(br, 12H), 1.01–0.93 (m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 174.3, 134.4,133.7, 131.9, 131.3, 128.7, 118.9, 80.5, 79.1, 76.0, 51.4, 37.7, 36.4,35.5, 35.1, 34.5, 34.1, 30.0, 29.3, 29.2, 29.1, 27.6, 24.9, 24.2, 22.7,17.9, 16.7, 15.1, 4.5; LRMS (API-ES) 529 (M+Na)⁺, 507, 489, 471, 453;[α]²⁰ _(D) +27.3 (c 0.43, CHCl₃).

(12S,13S,14S,19R,20R,21R,22S)-13,19,21-Trihydroxy-12,14,20,22-tetramethylhexacosa-10,15,23,25-tetraenoicacid (49). To an above solution 48 (8.0 mg) in THF-H₂O (0.3 ml, 0.1 mleach) was added LiOH.H₂O (1.3 mg) and the solution was warmed to 60° C.After stirring 6 h, 1N HCl (1 ml) was added and reaction mixture wasextracted with CH₂Cl₂ (10 ml×2). After drying over MgSO₄ and evaporationunder vacuum, the crude was chromatographed on SiO₂ (EtOAc/hexane 1:3)to yield 6.3 mg (81%) of the 49 as a colorless oil: IR (CHCl₃) 3412,2964, 2921, 2850, 2658, 1710, 1459, 1404, 1268, 971, 903 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 6.64 (ddd, J=16.7, 10.6, 10.0 Hz, 1H), 6.20 (apparentt, J=10.9 Hz, 1H), 5.54–5.46 (m, 1H), 5.42–5.36 (m, 2H), 5.32–5.18 (m,4H), 3.88–3.84 (m, 1H), 3.48 (d, J=9.2 Hz, 1H), 3.23 (apparent t, J=5.7Hz, 1H), 2.86–2.76 (m, 1H), 2.69–2.60 (m, 2H), 2.34 (t, J=7.4 Hz, 2H),2.21–2.04 (m, 5H), 1.70–1.62 (m, 5H), 1.28 (br, 13H), 1.00 (d, J=6.8 Hz,3H), 0.98 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 180.6, 134.4, 133.8, 132.1, 132.0, 132.0, 131.3, 128.8, 119.1,80.7, 79.2, 76.2, 37.6, 35.5, 34.6, 29.8, 29.7, 29.5, 29.2, 29.1, 29.0,27.6, 24.8, 24.2, 22.8, 18.1, 16.7, 15.4, 14.2, 4.5; LRMS (API-ES) 515.3(M+Na)⁺, 493 (M+H)⁺, 475 (M+H-H₂O)⁺, 457 (M+H-2H₂O)⁺, 242; [α]²⁰ _(D)+33.0 (c 0.23, CHCl₃).

(4R,5R)-5-(4-Methoxybenzyloxy)-4-methyl-8-oxooct-2-enoic acid ethylester (51). To a cooled (0° C.) stirred suspension of NaH (2.27 g, 11.3mmol, 60% dispersion in mineral oil) in THF (130 ml) was added dropwisea solution of triethyl phosphonoacetate (2.27 ml, 11.4 mmol) over 10 minperiod. The mixture was brought to room temperature with a water bath(30 min) and then cooled back to 0° C. and the aldehyde from 50 (3.43 g,9.0 mmol) in THF (10 ml) was added. The resulting mixture was stirredfor 1 h at 0° C. then pH7 phosphate buffer solution (30 ml) and diethylether (100 ml) were added. The mixture was allowed to warm to roomtemperature and the phase was separated. The organic phase was washedwith sat'd NH₄Cl solution (30 ml) and brine (30 ml), dried with MgSO₄,filtered and concentrated to give oily crude product. Purification byflash chromatography (EtOAc/hexane 1:4) afforded pure ester (3.82 g,94%): IR (CHCl₃) 2954, 2928, 2855, 1720, 1513, 1250, 1034, 835 cm⁻¹; ¹HNMR (300 MHz, CDCl₃)

{tilde over (□)}□9–7.25. m, 2H), 7.00 (dd, J=15.7, 7.5 Hz, 1H),6.91–6.84 (m, 2H), 5.83 (d, J=15.7 Hz, 1H), 4.47 (dd, J=14.6, 11.1 Hz,2H), 4.19 (q, J=7.1 Hz, 2H), 3.81 (s, 3H), 3.64–3.52 (m, 2H), 3.37–3.33(m, 1H), 2.64 (dd, J=13.2, 6.5 Hz, 1H), 1.42–1.68 (m, 4H), 1.30 (t,J=7.1 Hz, 3H), 1.09 (d, J=6.7 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³CNMR (75 MHz, CDCl₃) δ 166.7, 159.3, 151.2, 130.8, 130.4, 129.5, 121.3,113.9, 81.8, 71.6, 63.1, 60.3, 55.3, 39.8, 28.9, 27.7, 26.1, 18.5, 15.1,14.4, −5.1; LRMS (API-ES) 489.1 (M+K)⁺, 435, 263, 204; [α]²⁰ _(D) +6.4(c 0.43, CHCl₃).

To a solution of above TBS ether (0.324 g, 0.72 mmol) in THF (5 ml) wasslowly added HF-pyridine in pyridine (8 ml, prepared by slow addition of2.4 ml pyridine to 0.6 ml HF-pyridine complex followed by dilution with5 ml THF). The mixture was stirred overnight at room temperature andquenched with sat'd NaHCO₃ (20 ml). The aqueous layer was separated andextracted with CH₂Cl₂ (3×10 ml). The combined organic layer was washedwith sat'd CuSO₄ (3×20 ml), dried over MgSO₄, and concentrated. Flashcolumn chromatography (EtOAc/hexane 1:3) afforded 0.203 g (84%) of thealcohol: IR (CHCl₃) 1715, 1612, 1514, 1249, 1180, 1035 cm⁻¹; ¹H NMR (300MHz, CDCl₃)

{tilde over (□)}□7–7.24. m, 2H), 6.98 (dd, J=15.8, 7.5 Hz, 1H),6.88–6.85 (m, 2H), 5.83 (d, J=15.8 Hz, 1H), 4.47 (dd, J=14.6, 11.1 Hz,2H), 4.17 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 3.59–3.56 (m, 2H), 3.37–3.33(m, 1H), 2.71–2.65 (m, 1H), 2.15 (br, 1H), 1.77–1.40 (m, 4H), 1.28 (t,J=7.1 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.7,159.3, 150.8, 130.4, 129.6, 121.4, 113.9, 81.9, 71.7, 62.8, 60.4, 55.3,39.5, 28.9, 27.8, 15.2, 14.4; LRMS (API-ES) 375.1 (M+K)⁺, 359.1 (M+Na)⁺,241, 225; [α]²⁰ _(D) +12.0 (c 0.15, CHCl₃).

The above alcohol (0.203 g, 0.61 mmol) in CH₂Cl₂ (6 mL) was treated withDess-Martin periodinane (0.38 g, 0.90 mmol). After 2 h, the mixture wasquenched with saturated NaHCO₃ (10 mL). The aqueous layer was extractedwith ethyl ether (10 mL×2) and the combined extracts were dried overanhydrous MgSO₄. Filtration and concentration followed by short flashcolumn chromatography (hexane/EtOAc 3:1) to remove the residue fromDess-Martin reagent provided 0.146 g (72%) of the crude aldehyde 51 as acolorless oil which was used for the next reaction without furtherpurification: ¹H NMR (300 MHz, CDCl₃) δ 9.68 (s, 1H), 7.27–7.21 (m, 2H),6.99 (dd, J=15.8, 7.3 Hz, 1H), 6.88–6.85 (m, 2H), 5.84 (d, J=15.8 Hz,1H), 4.48 (d, J=11.0 Hz, 1H), 4.34 (d, J=11.0 Hz, 1H), 4.18 (q, J=7.1Hz, 2H), 3.79 (s, 3H), 3.41–3.31 (m, 1H), 2.73–2.63 (m, 1H), 2.55–2.40(m, 1H), 1.90–1.78 (m, 1H), 1.71–1.61 (m, 1H), 1.28 (t, J=7.1 Hz, 3H),1.27–1.22 (m, 2H), 1.10 (d, J=6.8 Hz, 3H).

(4R,5R,10S,11S,12S,17R,18R,19R,20S)-19-(tert-Butyldimethylsilanyloxy)-5,11,17-tris-(4-methoxybenzyloxy)-4,10,12,18,20-pentamethyltetracosa-2,8,13,21,23-pentaenoicacid ethyl ester (52). NaHMDS (1.0 M in THF, 0.49 mL, 0.49 mmol) wasslowly added to a solution of the salt 21 (0.35 g, 0.55 mmol) in dry THF(0.50 mL) at 0° C. The resulting red solution was stirred at roomtemperature for 20 min. The mixture was cooled to −78° C. and a solutionof the aldehyde 51 (146 mg, 0.44 mmol) in THF (0.1 mL) was addeddropwise. The mixture was stirred for 20 min at −78° C. and then warmedto room temperature. After 4 h at room temperature, the mixture wasquenched with saturated NH₄Cl (2 mL) and extracted with ethyl ether(3×10 mL). The combined organic layers were dried over anhydrous MgSO₄,evaporated and the residue was flash column chromatographed(hexane/EtOAc 9:1) to yield (183 mg, 74%) as a colorless oil: IR (CHCl₃)2962, 2850, 1716, 1614, 1515, 1249, 1179, 1035 cm⁻¹; ¹H NMR (300 MHz,CDCl₃)

{tilde over (□)}□6–7.49. m, 2H), 7.41–7.36 (m, 2H), 7.12 (dd, J=15.8,7.5 Hz, 1H), 7.00–6.97 (m, 4H), 5.95 (d, J=15.8 Hz, 1H), 5.56 (s, 1H),5.52–5.39 (m, 2H), 4.53 (d, J=3.0 Hz, 2H), 4.33 (q, J=7.1 Hz, 2H),4.22–4.14 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.69 (dd, J=9.6, 1.9 Hz,1H), 3.46–3.40 (m, 1H), 2.88–2.80 (m, 1H), 2.75–2.67 (m, 1H), 2.36–2.14(m, 2H), 1.84–1.81 (m, 1H), 1.67–1.55 (m, 2H), 1.43 (t, J=7.1 Hz, 3H),1.32 (d, J=6.9 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ 166.8, 159.8, 159.3, 151.3, 134.0, 131.8,130.9, 129.7, 129.5, 127.4, 121.1, 113.9, 113.5, 101.7, 83.9, 81.5,74.0, 71.7, 60.3, 55.4, 39.7, 33.8, 31.5, 30.1, 23.9, 16.1, 15.0, 14.4,11.2; LRMS (API-ES) 605.3 (M+K)⁺, 589.3 (M+Na)⁺, 567.3 (M+H)⁺; [α]²⁰_(D) +30.0 (c 0.01, CHCl₃).

Trimethylsilyl chloride (0.24 ml, 1.9 mmol) was added dropwise to astirred mixture containing above acetal (0.177 g, 0.31 mmol), NaCNBH₃(0.12 g, 1.9 mmol) and 4A molecular sieve in acetonitrile (6 ml) at 0°C. The reaction mixture was stirred for 1 h at 0° C. and filteredthrough Celite, poured into 1N HCl (10 ml). The aqueous phase wasextracted by CH₂Cl₂ (2×20 ml), dried (MgSO₄), filtered and concentrated.The residue was purified by column chromatography on silica gel(EtOAc/hexane 1:3) to yield the alcohol (0.121 g, 68%) as a colorlessoil: IR (CHCl₃) 3467, 2962, 2931, 2873, 1716, 1612, 1514, 1462, 1248,1179, 1035 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.26–7.24 (m, 4H), 6.98 (dd,J=15.7, 7.6 Hz, 1H), 6.91–6.85 (m, 4H), 5.83 (d, J=15.7 Hz, 1H), 5.48(dd, J=10.8, 9.6 Hz, 1H), 5.41–5.33 (m, 1H), 4.58 (d, J=12.7 Hz, 1H),4.46 (d, J=11.9 Hz, 3H), 4.19 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.79 (s,3H), 3.63–3.49 (m, 2H), 3.39–3.29 (m, 2H), 2.78 (dd, J=15.7, 6.8 Hz,1H), 2.61 (dd, J=13.1, 6.6 Hz, 1H), 2.23–2.17 (m, 1H), 2.09–1.94 (m,3H), 1.58–1.44 (m, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H),0.96 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)δ 166.8, 159.2, 151.1, 133.6, 131.1, 130.7, 129.5, 129.1, 128.7, 121.3,114.0, 113.9, 113.8, 84.3, 81.6, 73.9, 71.6, 66.2, 60.4, 55.4, 39.7,37.7, 34.8, 31.5, 23.8, 18.7, 15.1, 14.4, 11.5; LRMS (API-ES) 591.2(M+Na)⁺, 569.3 (M+H)⁺, 551; [α]²⁰ _(D) +37.2 (c 0.39, CHCl₃).

The same procedure for 45 was used with above alcohol (0.088 g, 0.16mmol) to yield 64 mg (42% for 2 steps) of the 52 by flash columnchromatography (EtOAc/hexane 1:5): IR (CHCl₃) 2956, 2932, 2857, 1717,1612, 1513, 1462, 1301, 1248, 1172, 1037, 835, 773 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 7.29–7.23 (m, 6H), 6.98 (dd, J=15.9, 7.6 Hz, 1H),6.89–6.85 (m, 6H), 6.40 (ddd, J=16.8, 10.6, 10.5 Hz, 1H), 5.96 (apparentt, J=10.9 Hz, 1H), 5.83 (d, J=15.8 Hz, 1H), 5.47 (apparent q, J=10.6 Hz,1H), 5.36–5.24 (m, 4H), 5.15 (d, J=16.8 Hz, 1H), 5.05 (d, J=9.9 Hz, 1H),4.58–4.32 (m, 6H), 4.20 (q, J=7.1 Hz, 2H), 3.81 (s, 6H), 3.80 (s, 3H),3.58–3.57 (m, 1H), 3.30–3.28 (m, 2H), 3.06–3.04 (m, 1H), 2.71–2.65 (m,2H), 2.62–2.56 (m, 2H), 2.19–2.17 (m, 2H), 2.06–1.88 (m, 4H), 1.76–1.42(m, 6H), 1.30 (t, J=7.1 Hz, 3H), 1.07–0.97 (m, 12H), 0.92 (s, 9H), 0.06(s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 166.7, 159.2, 159.1, 151.2, 134.8,133.8, 132.9, 132.5, 131.4, 130.7, 129.5, 129.2, 128.9, 128.6, 121.2,117.3, 113.8, 113.7, 88.0, 81.6, 78.9, 74.9, 71.6, 70.9, 60.3, 55.4,40.0, 39.7, 36.5, 35.5, 35.4, 31.6, 31.4, 26.3, 23.7, 20.8, 19.0, 18.8,18.6, 17.2, 15.0, 14.4, 11.1, −3.2; LRMS (API-ES) 1034.2 (M+K)⁺, 1017.6(M+Na)⁺, 995.7 (M+H)⁺; [α]²⁰ _(D) +40.7 (c 4.09, CHCl₃).

(6R,7R,12S,13S,14S,19R,20R,21R,22S)-21-(tert-Butyldimethylsilanyloxy)-7,13,19-tris-(4-methoxybenzyloxy)-6,12,14,20,22-pentamethylhexacosa-2,4,10,15,23,25-hexaenoicacid methyl ester (53). To the above ester 52 (64 mg. 64 μmol) in CH₂Cl₂(2 ml) was added DIBAL-H (0.16 ml, 0.16 mmol, 1.0 M solution in hexane)at −78° C. dropwise and then warmed up to 0° C. and stirred for 1 h. Thereaction mixture was quenched by EtOAc (2 ml) and sat'd sodium potassiumtartrate solution (20 mL) followed by vigorously stirring for 4 h. Theaqueous phase was extracted with CH₂Cl₂ (3×10 mL) and the combinedorganic layers were washed with brine (10 mL). After drying over MgSO₄and evaporation under vacuum, flash column chromatography (hexane/EtOAc3:1) provided 47 mg of alcohol (77%) as a colorless oil: IR (CHCl₃)3429, 2956, 2857, 2360, 1613, 1513, 1463, 1248, 1037, 835 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 7.43–7.37 (m, 6H), 7.03–6.98 (m, 6H), 6.53 (ddd,J=16.8, 10.6, 10.5 Hz, 1H), 6.10 (apparent t, J=11.0 Hz, 1H), 5.81–5.77(m, 2H), 5.64 (d, J=10.4 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 5.18 (d,J=10.1 Hz, 1H), 4.72–4.45 (m, 6H), 4.21 (q, J=3.2 Hz, 2H), 3.94 (s, 6H),3.93 (s, 31H), 3.71 (dd, J=5.6, 3.0 Hz, 1H), 3.41 (dd, J=10.5, 5.2 Hz,1H), 3.33 (dd, J=11.1, 6.4 Hz, 1H), 3.19 (dd, J=12.1, 5.9 Hz, 1H),2.36–2.19 (m, 2H), 2.12–2.02 (m, 3H), 1.87–1.59 (m, 5H), 1.16–1.13 (m,9H), 1.07–1.05 (m, 6H), 1.04 (s, 9H), 0.19 (s, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 159.3, 159.2, 159.1, 135.1, 134.8, 133.9, 132.7, 132.6, 131.5,131.1, 129.7, 129.5, 129.3, 129.2, 128.8, 128.6, 117.4, 114.1, 113.8,88.1, 82.5, 79.0, 74.9, 71.5, 70.9, 65.2, 64.0, 55.4, 40.0, 39.4, 36.6,35.6, 35.4, 31.4, 29.9, 26.4, 23.9, 23.7, 19.1, 18.8, 18.7, 17.3, 16.1,11.1, −3.1, −3.2; LRMS (API-ES) 991.6 (M+K)⁺, 975.6 (M+Na)⁺; [α]²⁰ _(D)+38.3 (c 1.05, CHCl₃).

The above alcohol (47 mg, 49 μmol) in CH₂Cl₂ (2 mL) was treated withDess-Martin periodinane (31 mg, 73 μmol). After 2 h, the mixture wasquenched with saturated NaHCO₃ (5 mL). The aqueous layer was extractedwith ethyl ether (5 mL×2) and the combined extracts were dried overanhydrous MgSO₄. Filtration and concentration followed by short flashcolumn chromatography filtration (hexane/EtOAc 3:1) to remove theresidue from Dess-Martin reagent provided crude aldehyde as a colorlessoil which was used for the next reaction without further purification.To a stirred solution ofbis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl) phosphate (0.013 ml,59 mmol), 18-crown-6 (0.065 g, 0.25 mmol) in THF (1 ml) cooled to −78°C. was added dropwise potassium bis(trimethylsilyl)amide (0.12 ml, 59μmol, 0.5M solution in toluene). Thereafter the above aldehyde in THF (1ml) was added and the solution was stirred for 6 h at −78° C. Thereaction mixture was quenched by addition of a sat'd NH₄Cl solution (1ml) and diluted with diethyl ether (10 ml). The layer was separated andorganic phase was washed with brine (10 ml) and dried with MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (EtOAc/Hexane 1:5), yielding 40 mg of (E,Z)-doublyunsaturated ester 53 (85% for 2 steps): IR (CHCl₃) 2956, 2856, 1717,1612, 1513, 1462, 1301, 1248, 1173, 1037, 820 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 7.53 (dd, J=15.4, 11.3 Hz, 1H), 7.43–7.37 (m, 6H), 7.03–6.98(m, 6H), 6.68 (dd, J=11.4, 11.3 Hz, 1H), 6.53 (ddd, J=17.0, 10.7, 10.4Hz, 1H), 6.19 (dd, J=15.4, 7.6 Hz, 1H), 6.09 (apparent t, J=11.2 Hz,1H), 5.73 (d, J=11.4 Hz, 1H), 5.64 (d, J=10.3 Hz, 1H), 5.56 (d, J=11.0Hz, 1H), 5.45–5.41 (m, 3H), 5.28 (d, J=15.3 Hz, 1H), 5.18 (d, J=10.0 Hz,1H), 4.71–4.45 (m, 6H), 3.94 (s, 6H), 3.93 (s, 3H), 3.87 (s, 3H), 3.70(dd, J=6.1, 3.2 Hz, 1H), 3.44–3.38 (m, 1H), 3.19 (dd, J=6.9, 4.2 Hz,1H), 2.85–2.77 (m, 3H), 2.34–2.31 (m, 2H), 2.08–2.04 (m, 3H), 1.84–1.55(m, 5H), 1.20 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.9 Hz, 3H), 1.12 (d, J=8.2Hz, 3H), 1.07–1.01 (m, 15H), 0.16 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ166.9, 159.1, 158.9, 147.6, 145.6, 134.7, 133.7, 132.7, 132.4, 131.3,130.9, 130.8, 129.5, 129.4, 129.0, 128.9, 128.4, 126.4, 117.2, 115.4,113.7, 87.9, 82.1, 78.8, 74.7, 71.4, 70.8, 55.2, 53.4, 51.1, 40.0, 36.4,35.4, 35.2, 31.4, 31.3, 29.7, 26.2, 23.7, 23.6, 18.9, 18.6, 18.5, 17.1,15.4, 10.9, −3.3, −3.4; LRMS (API-ES) 1045.5 (M+K)⁺, 1029.5 (M+Na)⁺;[α]²⁰ _(D) +35.3 (c 0.96, CHCl₃).

(7R,8R,13S,14S,15S,20R,21R,22R,23S)-8,14,20-Trihydroxy-7,13,15,21-tetramethyl-22-(1-methylpenta-2,4-dienyl)-oxacyclodocosa-3,5,11,16-tetraen-2-one(54). To a stirred solution of protected alcohol 53 (33 mg, 33 μmol) inTHF (1 ml) at 0° C. was added 2 ml of 3 N HCl (prepared by adding 25 mlof conc. HCl to 75 ml MeOH). After 6 h, the reaction mixture was dilutedwith EtOAc (5 ml) and H₂O (5 ml) and the organic phase was separated andaqueous phase was extracted with EtOAc (2×5 ml). The combined organicphase was washed with sat'd NaHCO₃ (10 ml), dried with MgSO₄,concentrated and the residue was purified by flash chromatography(EtOAc/Hexane 1:4) to yield 19 mg (21 mmol) of product (63%): IR (CHCl₃)3491, 2958, 2869, 1716, 1612, 1513, 1456, 1248, 1036 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 7.40 (dd, J=15.3, 11.5 Hz, 1H), 7.29–7.22 (m, 6H),6.92–6.84 (m, 6H), 6.61 (ddd, J=17.7, 10.7, 10.4 Hz, 1H), 6.54 (dd,J=11.5, 11.4 Hz, 1H), 6.10 (apparent t, J=11.0 Hz, 1H), 6.06 (dd,J=15.1, 7.7 Hz, 1H), 5.59 (d, J=11.3 Hz, 1H), 5.49 (d, J=10.4 Hz, 1H),5.41 (d, J=10.6 Hz, 1H), 5.37–5.30 (m, 3H), 5.21 (d, J=17.0 Hz, 1H),5.11 (d, J=10.2 Hz, 1H), 4.58–4.34 (m, 6H), 3.81 (s, 3H), 3.80 (s, 3H),3.79 (s, 3H), 3.73 (s, 3H), 3.47–3.44 (m, 2H), 3.31–3.25 (m 1H), 3.05(dd, J=7.3, 4.0 Hz, 1H), 2.80–2.69 (m, 2H), 2.66–2.61 (m, 1H), 2.20–2.15(m, 2H), 2.05–1.91 (m, 3H), 1.85–1.76 (m, 1H), 1.72–1.61 (m, 2H),1.57–1.47 (m, 2H), 1.09 (d, J=6.8 Hz, 3H), 1.00 (apparent q, J=7.1 Hz,9H), 0.91 (d, J=6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.1, 159.3,159.1, 147.7, 145.7, 136.8, 134.1, 132.8, 132.5, 131.4, 132.8, 132.5,131.4, 130.9, 130.4, 130.2, 129.6, 129.3, 128.3, 126.6, 118.0, 115.6,114.0, 113.9, 88.1, 83.1, 82.2, 75.0, 71.5, 71.0, 55.4, 51.2, 40.1,36.7, 36.3, 35.9, 35.4, 31.6, 30.6, 29.9, 23.9, 23.8, 19.0, 17.6, 15.6;LRMS (API-ES) 915.5 (M+Na)⁺; [α]²⁰ _(D) +41.1 (c 0.45, CHCl₃).

To the stirred solution of above ester (19 mg, 21 μmol) in EtOH (1 ml)was added 1N aqueous KOH solution (0.056 ml) and the mixture wasrefluxed gently until the ester disappeared (about 6 h) as determined byTLC. The ethanolic solution was concentrated and then diluted with EtOAc(2 ml). After the solution was acidified to pH3 with 1N HCl solution,organic phase was separated and aqueous phase was extracted with EtOAc(2×5 ml). The combined organic phase were dried with MgSO₄, concentratedand used as crude without further purification. The same procedure for43 was used with above acid compound to yield 14 mg (79% for 2 steps) ofthe macrolactone product by flash column chromatography (EtOAc/hexane1:3): IR (CHCl₃) 2961, 2869, 1708, 1612, 1513, 1462, 1248, 1174, 1076,1036, 820, 755 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.41–7.38 (m, 7H),7.03–6.96 (m, 6H), 6.73–6.57 (m, 1H), 6.67 (apparent t, J=11.2 Hz, 1H),6.31 (dd, J=15.8, 6.4 Hz, 1H), 6.12 (apparent t, J=11.0 Hz, 1H), 5.69(d, J=11.1 Hz, 1H), 5.53–5.40 (m, 3H), 5.34–5.19 (m, 4H), 4.70–4.47 (m,6H), 3.94 (s, 6H), 3.89 (s, 3H), 3.43–3.38 (m, 1H), 3.26–3.16 (m 2H),3.08–3.03 (m, 1H), 2.87–2.86 (m, 1H), 2.78–2.73 (m, 2H), 2.22–2.19 (m,2H), 2.07–2.05 (m, 3H), 1.93–1.55 (m, 5H), 1.23 (d, J=6.9 Hz, 3H), 1.19(d, J=7.2 Hz, 9H), 1.07 (d, J=6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ166.3, 159.2, 158.9, 145.4, 143.6, 134.0, 133.0, 132.2, 131.4, 130.8,130.7, 129.9, 129.53, 128.48, 129.43, 129.4, 129.3, 129.2, 129.0, 126.2,117.7, 116.9, 113.8, 113.6, 88.0, 83.2, 75.2, 71.7, 71.2, 55.2, 39.4,38.4, 37.0, 35.6, 34.3, 31.7, 25.4, 24.9, 19.7, 18.6, 17.2, 15.4, 10.0;LRMS (API-ES) 899.5 (M+K)⁺, 883.5 (M+Na)⁺; [α]²⁰ _(D) +40.4 (c 0.47,CHCl₃).

The same procedure for 43 was used with above lactone (14 mg, 16 μmol)to yield 3.7 mg (46%) of the product 54 by flash column chromatography(EtOAc/hexane 1:2): IR (CHCl₃) 3411, 2964, 2926, 2872, 1692, 1637, 1435,1182, 999, 962 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.27 (ddt, J=15.7, 11.2,1.2 Hz, 1H), 6.61 (ddt, J=16.8, 1.1, 10.7 Hz, 1H), 6.53 (apparent t,J=11.3 Hz, 1H), 6.02 (dd, J=15.4, 6.7 Hz, 1H), 6.01 (apparent t, J=11.0Hz, 1H), 5.56 (d, J=11.5 Hz, 1H), 5.43 (dd, J=10.8, 9.1 Hz, 1H),5.39–5.36 (m, 1H), 5.33 (apparent t, J=10.6 Hz, 1H), 5.30–5.23 (m, 2H),5.19 (dt, J=16.8, 0.9 Hz, 1H), 5.10 (d, J=10.1 Hz, 1H), 5.00 (dd, J=7.8,3.2 Hz, 1H), 3.67 (ddd, J=11.7, 5.8, 4.6 Hz, 1H), 3.41 (ddd, J=8.9, 6.0,2.4 Hz, 1H), 3.31 (dd, J=7.0, 5.0 Hz, 1H), 3.06–3.00 (m, 1H), 2.68–2.61(m, 2H), 2.41 (dd, J=13.7, 6.8 Hz, 1H), 2.20–2.11 (m, 2H), 1.82 (dt,J=7.2, 3.2 Hz, 1H), 1.77–1.71 (m, 2H), 1.41–1.35 (m, 2H), 1.32–1.25 (m,2H), 1.11 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.9 Hz, 3H), 1.03 (d, J=7.0 Hz,3H), 1.02 (d, J=7.0 Hz, 3H), 1.01 (d, J=6.7 Hz, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 166.5, 145.8, 143.5, 133.8, 132.3, 132.1, 131.5, 130.0, 129.8,129.7, 127.0, 117.9, 117.2, 79.3, 73.1, 72.7, 42.8, 40.4, 36.7, 35.0,34.9, 34.6, 33.7, 24.7, 24.0, 18.7, 17.8, 17.3, 15.3, 9.9; HRMS (EI)calcd for C₃₁H₄₇O₄ 482.3396 (M−OH)⁺, found 482.3416; [α]²⁰ _(D) +19.2 (c0.24, CHCl₃).

4(R)-Benzyl-3-[4-(2,2-dimethyl-[1,3(S)]dioxolan-4-yl)-3(S)-hydroxy-2(R)-methyl-butyryl]-oxazolidin-2-one(56). Diisopropylethylamine (13 ml) was added to a solution ofpropionyloxazolidinone (13.1 g) in anhydrous CH₂Cl₂ (250 ml) at 0° C.,followed by dropwise addition of nBu₂BOTf (1.0M in CH₂Cl₂, 68 ml). Thesolution was stirred for 1 h at 0° C. A solution of crude aldehyde from55 (8.9 g) prepared before in anhydrous CH₂Cl₂ (10 ml) was added slowlyat −78° C. After addition, the reaction mixture was warmed to 0° C. andstirred for 1 h then quenched with pH7 phosphate buffer (20 mL). Asolution of hydrogen peroxide (30%, 40 mL) in MeOH (80 mL) was added at0° C. and the mixture was allowed to stir for 1 h. The reaction mixturewas extracted with CH₂Cl₂ (50 mL×2) and dried over MgSO₄ followed byflash chromatography (EtOAc/hexane 1:1) to yield 20.7 g of product(98%): IR (CHCl₃) 3434, 2956, 2929, 2858, 1724, 1472, 1463, 1257, 1097,836, 775 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

7.33. m, 3H), 7.22 (m 2H), 4.72 (ddd, J=10.5, 6.9, 3.2 Hz, 1 H), 4.35(m, 1H), 4.23 (m, 3H), 4.12 (dd, J=8.5, 6.5 Hz, 1H), 3.82 (ddd, J=10.2,7.0, 3.2 Hz, 1H), 3.61 (t, J=7.7 Hz, 1H), 3.25 (dd, J=13.4, 3.3 Hz, 1H),2.82 (dd, J=13.4, 9.4 Hz, 1H), 1.80 (ddd, J=14.2, 9.7, 4.6 Hz, 1H), 1.68(ddd, J=10.8, 7.8, 3.0 Hz, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.30 (d,J=7.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.9, 152.9, 134.9, 129.3,128.8, 127.3, 108.6, 73.4, 69.5, 68.5, 66.0, 54.9, 42.4, 37.5, 26.8,25.6, 14.1, 10.8; [α]²⁰ _(D) −28.1 (c 4.1, CHCl₃).

6-(2,2-Dimethyl-[1,3(S)]dioxolan-4-yl)-5(S)-hydroxy-4(R)-methyl-hex-2-enoicacid ethyl ester (57). To a solution of RED-Al (4.6 ml) in THF (100 ml)at −78° C. was added aldol product 56 (5.39 g) in THF (10 ml) slowlyover 10 min. The evolution of gas could be seen as the solution wasstirred for 10–15 min at −78° C. The reaction was then warmed to −50° C.and stirred between −55 and −40° C. for 1 h. The reaction was quenchedat −50° C. with 100 ml of EtOAc and 10 ml of MeOH and then poured into amixture of sat'd Rochelle salt (30 ml) and Et₂O (60 ml) and stirred at−20° C. for 10 min. The aqueous layer froze as a gel. The ether layerwas separated and the aqueous layer rinsed quickly with Et₂O (2×30 ml).The combined organic extracts were dried over MgSO₄ and concentrated invacuo. The crude aldehyde was taken immediately on to the Wittigreaction. To a 200 ml of dry THF was added 3.26 ml oftriethylphosphonoacetate, followed by 1.86 g of potassium tert-butoxide.The mixture was stirred at room temperature for 10 min before cooling to−78° C. The crude aldehyde was added in 20 ml of THF and stirredovernight while warming to room temperature. The mixture was poured into30 ml of brine, extracted with Et₂O (3×40 ml), dried over MgSO₄ andconcentrated in vacuo. Flash silica gel chromatography (hexane/EtOAc3:2) provided 2.02 g (52% for 2 steps) of pure product as an colorlessoil: ¹H NMR (300 MHz, CDCl₃)

6.88 (dd, J=15.8, 8.0 Hz, 1H), 5.83 (d, J=15.8 Hz, 1H), 4.28 (m, 1H),4.14 (q, J=7.1 Hz, 1H), 4.03 (dd, J=8.1, 6.0 Hz, 1H), 3.76 (m, 1H), 3.53(t, J=8.0 Hz, 1H), 2.48 (brs, 1H), 2.41 (m, 1H), 1.72˜1.56 (m, 2H), 1.37(s, 3H), 1.31 (s, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.07 (d, J=6.8 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ 166.4, 150.3, 121.6, 108.6, 73.5, 71.3, 69.3,60.2, 42.8, 37.2, 25.8, 25.5, 14.5, 14.1.

5(S),7(S),8-Tris-(tert-butyl-dimethyl-silanyloxy)-4(R)-methyl-oct-2-enoicacid ethyl ester (58). To a stirred solution of conjugated ester 57(1.73 g) in MeOH (20 ml) was added Dowex HCR-W2 ion-exchange resin (2.0g, activated by aqueous 1N HCl for 24 h then filtered, MeOH as eluent)and stirred for 24 h. The resin was filtered and filtrate wasconcentrated and dried for 2 h in vacuo. The triol was then used in nextstep without further purification. To a stirred solution of triol and2,6-lutidine (3.3 mL, 28.6 mmol) in CH₂Cl₂ (30 mL) at 0° C. was addedTBDMSOTf (5.1 mL, 22.2 mmol) and the reaction mixture was stirred for 1h at 0° C. The reaction mixture was quenched by the addition of water(25 mL). The reaction mixture was extracted by CH₂Cl₂ and dried overMgSO₄ followed by the evaporation of the solvent under reduced pressure.The residue was purified by short column chromatography (hexane/EtOAc9:1) whereupon the 58 (2.96 g, 81% for 2 steps) was obtained: ¹H NMR(300 MHz, CDCl₃)

7.04 (dd, J=15.9, 6.7 Hz, 1H), 5.75 (dd, J=15.9, 1.5 Hz, 1H), 4.16 (dq,J=1.3, 7.1 Hz, 2H), 3.84 (quint, J=3.6 Hz, 1H), 3.71 (m, 1 H), 3.49 (dd,J=10.1, 5.4 Hz, 1H), 3.36 (dd, J=10.1, 5.8 Hz, 1H), 2.48 (m, 1H),1.59˜1.40 (m, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H), 0.85(m, 27H), 0.056 (s, 3H), 0.049 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H), 0.01(s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 166.6, 151.7, 120.8, 72.8, 71.4,68.0, 60.0, 42.2, 39.5, 25.9, 25.7, 18.3, 18.1, 14.2, 13.3, −3.0, −3.6,−4.2, −4.5, −5.4.

5(S),7(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-8-hydroxy-4(R)-methyl-oct-2-enoicacid ethyl ester (59) To a solution of TBS ether 58 (7.4 g, 12.9 mmol)in THF (10 ml) was slowly added HF-pyridine in pyridine (40 ml, preparedby slow addition of 12 ml pyridine to 3 ml HF-pyridine complex followedby dilution with 25 ml THF). The mixture was stirred overnight at roomtemperature and quenched with sat'd NaHCO₃ (100 ml). The aqueous layerwas separated and extracted with Et₂O (3×50 ml). The combined organiclayers were washed with sat'd CuSO₄ (3×50 ml), dried over MgSO₄, andconcentrated. Flash column chromatography (EtOAc/Hexane 1:4) afforded3.86 g (65%) of the alcohol 59: IR (CHCl₃) 3492, 2956, 2930, 2857, 1722,1472, 1367, 1256, 1092, 1039, 836, 775 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

7.01. dd, J=15.9, 6.7 Hz, 1H), 5.75 (dd, J=15.9, 1.5 Hz, 1H), 4.15 (dq,J=1.2, 7.2 Hz, 2H), 3.75 (m, 1H), 3.56 (m, 1H), 3.40 (m, 1H), 2.44 (m,1H), 1.85 (t, J=5.9 Hz, 1H), 1.61 (ddd, J=11.5, 6.4, 5.0 Hz, 1H), 1.50(ddd, J=13.0, 7.2, 5.8 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.99 (d, J=6.9Hz, 3H), 0.86 (s, 9H), 0.85 (s, 9H), 0.60 (s, 6H), 0.34 (s, 3H), 0.02(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 151.1, 121.1, 72.8, 71.0,66.9, 60.1, 41.8, 38.7, 25.8, 18.0, 14.2, 13.3, −4.2, −4.3.

5(S),7(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-4(R)-methyl-8-oxo-oct-2-enoicacid ethyl ester (60). The alcohol 59 (3.86 g, 8.34 mmol) in CH₂Cl₂ (20mL) was treated with Dess-Martin periodinane (5.3 g, 12.5 mmol). After 1h, the mixture was quenched with saturated NaHCO₃ (50 mL). The aqueouslayer was extracted with ethyl ether (20 mL×2) and the combined extractswere dried over anhydrous MgSO₄. Filtration and concentration followedby short flash column chromatography (hexane/EtOAc 4:1) to remove theresidue from Dess-Martin reagent provided the aldehyde as a colorlessoil: ¹H NMR (300 MHz, CDCl₃)

9.53 (s, 1H), 7.02 dd, J=15.9, 6.6 Hz, 1H), 5.77 (dd, J=15.9, 1.4 Hz,1H), 4.15 (dq, J=1.0, 7.2 Hz, 2H), 4.07 (ddd, J=6.4, 4.8, 1.4 Hz, 1H),3.84 (ddd, J=8.6, 6. 8, 4.4 Hz, 1H), 2.52 (m, 1H), 1.66 (m, 2H), 1.25(t, J=7.1 Hz, 3H), 0.99 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H),0.07 (s, 3H), 0.05 (s, 3H), 0.03 (s, 6H).

5(S),7(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-10(S)-[2-(4-methoxy-benzyl)-5(S)-methyl-[1,3(R)]dioxan-4-yl]-4(R)-methyl-undeca-2,8-dienoicacid ethyl ester (61). NaHMDS (1.0 M in THF, 12.3 mL, 12.3 mmol) wasslowly added to a solution of the salt 21 (8.72 g, 13.7 mmol) in dry THF(13.7 mL) at 0° C. The resulting red solution was stirred at roomtemperature for 20 min. The mixture was cooled to −78° C. and a solutionof the aldehyde 60 (5.03 g, 10.9 mmol) in THF (2.0 mL) was addeddropwise. The mixture was stirred for 20 min at −78° C. and then warmedto room temperature. After 4 h at room temperature, the mixture wasquenched with saturated NH₄Cl (20 mL) and extracted with ethyl ether(3×30 mL). The combined organic layers were dried over anhydrous MgSO₄,evaporated and the residue was flash column chromatographed(hexane/EtOAc 9:1) to yield 61 (5.65 g, 75%) as a colorless oil: IR(CHCl₃) 2957, 2929, 2856, 1720, 1650, 1617, 1518, 1463, 1370, 1250,1158, 1073, 1032, 836, 774 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)

7.34. m, 2H), 6.99 (dd, J=15.8, 6.9 Hz, 1H), 6.82 (m, 2H), 5.72 (dd,J=15.8, 1.5 Hz, 1H), 5.36 (s, 1H), 5.32 (dd, J=11.1, 8.6 Hz, 1H), 5.18(t, J=10.8 Hz, 1H), 4.55 (ddd, J=12.6, 8.6, 4.1 Hz, 1H), 4.12 (m, 2H),3.99 (d, J=7.2, 2.1 Hz, 1H), 3.91 (m, 1H), 3.77 (s, 3H), 3.52 (dd,J=9.3, 2.1 Hz, 1H), 2.64 (m, 1H), 2.37 (m, 1H), 1.64 (m, 1H), 1.46 (m,2H), 1.22 (t, J=7.1 Hz, 3H), 1.15 (d, J=6.9 Hz, 3H), 0.93 (d, J=6.8 Hz,6H), 0.86 (s, 18H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 159.7, 151.9, 133.8, 132.7, 131.3,120.8, 113.4, 101.7, 83.6, 73.8, 71.9, 66.4, 60.0, 55.1, 43.6, 42.9,34.2, 29.8, 26.0, 25.9, 18.1, 15.6, 14.2, 13.5, 11.2, −3.0, −3.8, −4.1,−4.5; HRMS (ESI) calcd for C₃₆H₆₆O₇Si₂K 729.3984 (M+K)⁺, found 729.4013;[α]²⁰ _(D) −8.7 (c 6.8, CHCl₃).

5(S),7(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-10(S)-[2-(4-methoxy-benzyl)-5(S)-methyl-[1,3(R)]dioxan-4-yl]-4(R)-methyl-undeca-2,8-dien-1-ol(62). To the stirred solution of ester 61 (3.13 g, 4.53 μmol) in EtOH(20 ml), THF (2 ml) was added 1N aqueous KOH solution (45 ml) and themixture was refluxed gently until the ester disappeared (about 6 h) asdetermined by TLC. The ethanolic solution was concentrated and thendiluted with EtOAc (50 ml). After the solution was acidified to pH 3with 1N HCl solution, organic phase was separated and aqueous phase wasextracted with EtOAc (2×10 ml). The combined organic phase were driedwith MgSO₄, concentrated and used as crude in next step without furtherpurification. The carboxylic acid was treated with NEt₃ (1.5 ml) andethyl chloroformate (0.67 ml) in dry THF (50 ml) at −10° C. After 15min, the mixture was warmed to 0° C. and a solution of NaBH₄ (1.2 g) inH₂O (10 ml) were added. After 4 h, the reaction was quenched by additionof sat'd Rochelle salt solution and Et₂O. The layers were separated andthe organic layer was washed with H₂O, sat'd NaHCO₃ solution and brine,dried with MgSO₄. Rotary evaporation and silica column chromatography(hexane/EtOAc 4:1) gave product 62 (1.79 g, 61%) as a colorless oil: IR(CHCl₃) 3433, 2957, 2929, 2856, 1617, 1518, 1462, 1388, 1250, 1074, 836,773 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.38 (m, 2H), 6.84 (m, 2H), 5.63(dd, J=15.7, 6.2 Hz, 1H), 5.48 (dt, J=16.0, 5.6 Hz, 1H), 5.37 (t, J=10.6Hz, 1H), 4.59 (m, 1H), 3.99 (m, 2H), 3.93 (m, 1H), 3.87 (m, 2H), 3.77(s, 3H), 3.49 (dd, J=9.6, 2.0 Hz, 1H), 2.68 (m, 1H), 2.31 (m, 1H), 1.79(brs, 1H), 1.64 (m, 1H), 1.44 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.92 (d,J=6.9 Hz, 3H), 0.88 (m, 21H), 0.09 (s, 3H), 0.06 (s, 3H), 0.05 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ 159.6, 134.4, 134.3, 132.4, 131.5, 129.1,127.4, 113.4, 101.5, 83.5, 73.8, 72.8, 66.5, 63.7, 55.2, 42.2, 34.1,29.8, 26.1, 25.9, 18.14, 18.10, 15.5, 15.2, 11.3, −2.9, −4.1, −4.2; HRMS(ESI) calcd for C₃₆H₆₄O₆Si₂Na 671.4139 (M+Na)⁺, found 671.4141; [α]²⁰_(D) −14.0 (c 1.5, CHCl₃).

4-[4(S),6(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-1(S),7(R)-dimethyl-10-trityloxy-deca-2,8-dienyl]-2-(4-methoxy-benzyl)-5(S)-methyl-[1,3(R)]dioxane(63). To a solution of alcohol 62 (0.105 g) in pyridine (1.6 ml) wasadded trityl chloride (0.094 g) and DMAP (0.041 g). The mixture was thenrefluxed for 18 h, cooled to ambient temperature and added to a solutionof sat'd CuSO₄ (20 ml). The mixture was extracted with Et₂O (2×20 ml),washed sat'd CuSO₄ (2×20 ml). The organic layer was separated, dried(MgSO₄), filtered, and concentrated in vacuo. Flash columnchromatography (EtOAc/hexane 1:9) provided product 63 (0.142 g, 99%) asa pale yellow oil: IR (CHCl₃) 2956, 2926, 2855, 1616, 1517, 1462, 1378,1249, 1073, 835, 773, 705 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.63 (m, 6H),7.51 (m, 2H), 7.40 (m, 9H), 6.93 (m, 2H), 5.91 (dd, J=15.7, 6.5 Hz, 1H),5.66 (dt, J=15.5, 5.2 Hz, 1H), 5.55 (m, 1H), 5.53 (s, 1H), 5.39 (t,J=10.2 Hz, 1H), 4.78 (dt, J=3.1, 8.9 Hz, 1H), 4.10 (m, 3H), 3.80 (s,3H), 3.70 (m, 3H), 2.85 (m, 1H), 2.45 (m, 1H), 1.78 (m, 1H), 1.65 (m,2H), 1.31 (d, J=6.9 Hz, 3H), 1.08 (m, 24H), 0.28 (s, 3H), 0.27 (s, 3H),0.25 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 159.5, 146.8, 144.3, 135.0,134.1, 132.4, 131.3, 128.6, 127.8, 127.6, 127.3, 127.1, 126.7, 126.3,113.3, 101.5, 86.6, 83.4, 73.8, 72.7, 66.6, 65.0, 55.0, 43.5, 42.8,34.2, 29.9, 26.1, 25.9, 18.1, 15.7, 14.5, 11.3, −2.9, −3.8, −4.1, −4.3;HRMS (ESI) calcd for C₅₅H₇₈O₆Si₂K 929.4969 (M+K)⁺, found 929.5008; [α]²⁰_(D) −7.3 (c 1.1, CHCl₃).

7(S),9(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-3-(4-methoxy-benzyloxy)-2(S)(S),10(R)-trimethyl-13-trityloxy-trideca-5,11-dien-1-ol(64). To the PMB acetal 63 (3.75 g. 4.21 μmol) in CH₂Cl₂ (20 ml) wasadded DIBAL-H (21 ml, 21 mmol, 1.0 M solution in hexane) at −78° C.dropwise and then warmed up to 0° C. and stirred for 1 h. The reactionmixture was quenched by EtOAc (10 ml) and sat'd sodium potassiumtartrate solution (50 mL) followed by vigorously stirring for 4 h. Theaqueous phase was extracted with CH₂Cl₂ (3×20 mL) and the combinedorganic layers were washed with brine (30 mL). After drying over MgSO₄and evaporation under vacuum, flash column chromatography (hexane/EtOAc4:1) provided 64 (2.78 g, 74%) as a colorless oil: IR (CHCl₃) 3434,2956, 2928, 2856, 1612, 1514, 1471, 1249, 1073, 836, 774, 706 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.48 (m, 6H), 7.29 (m, 1H), 6.84 (m, 2H), 5.84(dd, J=15.7, 6.2 Hz, 1H), 5.57 (dt, J=15.7, 5.4 Hz, 1H), 5.44 (t, J=8.7Hz, 2H), 4.63 (m, 1H), 4.53 (d, J=10.9 Hz, 1H), 4.46 (d, J=10.9 Hz, 1H),3.94 (m, 1H), 3.80 (s, 3H), 3.57 (d, J=4.8 Hz, 2H), 3.48 (m, 1H), 3.31(m, 2H), 2.80 (m, 1H), 2.42 (m, 1H), 1.84 (m, 2H), 1.55 (ddd, J=14.2,10.1, 1.9 Hz, 1H), 1.40 (ddd, J=13.9, 8.6, 2.0 Hz, 1H), 1.07 (d, J=6.8Hz, 3H), 0.97 (m, 12H), 0.93 (s, 9H), 0.87 (d, J=7.0 Hz, 3H), 0.16 (s,3H), 0.15 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ159.0, 144.3, 134.0, 133.7, 131.5, 130.9, 129.3, 128.6, 127.9, 127.7,127.2, 126.8, 126.5, 113.6, 86.7, 84.0, 73.9, 73.0, 66.2, 65.8, 65.1,55.2, 42.3, 42.2, 38.0, 35.1, 26.0, 25.9, 18.5, 18.2, 18.1, 14.8, 12.0,−2.9, −4.0, −4.19, −4.23; HRMS (ESI) calcd for C₅₅H₈₀O₆Si₂K 931.5125(M+K)⁺, found 931.5152; [α]²⁰ _(D) −21.4 (c 0.52, CHCl₃).

9(S),11(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-5(R)-(4-methoxy-benzyloxy)-4(S),6(S),12(R)-trimethyl-15-trityloxy-pentadeca-2,7,13-trienoicacid ethyl ester (65). The alcohol 64 (2.01 g, 2.25 μmol) in CH₂Cl₂ (20mL) was treated with Dess-Martin periodinane (1.43 g, 3.4 μmol). After 1h, the mixture was quenched with saturated NaHCO₃ (20 mL). The aqueouslayer was extracted with ethyl ether (25 mL×2) and the combined extractswere dried over anhydrous MgSO₄. Filtration and concentration followedby short flash column chromatography filtration (hexane/EtOAc 3:1) toremove the residue from Dess-Martin reagent provided crude aldehyde as acolorless oil which was used for the next reaction without furtherpurification. To a stirred solution of triethyl phosphonoacetate (0.51ml, 2.60 □mol) in THF (20 ml) cooled to −78° C. was added dropwisepotassium tert-butoxide (0.29 g, 2.5 □mol) and stirred for 30 min.Thereafter the above aldehyde in THF (5 ml) was added and the solutionwas stirred for 1 h at −78° C., then 2 h at 0° C. The reaction mixturewas quenched by addition of a sat'd NH₄Cl solution (5 ml) and dilutedwith diethyl ether (20 ml). The layer was separated and organic phasewas washed with brine (20 ml) and dried with MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography(EtOAc/Hexane 1:9), yielding 2.01 g of unsaturated ester 65 (93% for 2steps): IR (CHCl₃) 2956, 2929, 2856, 1718, 1650, 1612, 1514, 1448, 1250,1180, 1074, 836, 774, 706 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55 (m, 6H),7.34 (m, 11H), 7.09 (dd, J=15.8, 7.1 Hz, 1H), 6.89 (m, 2H), 5.89 (dd,J=15.7, 5.8 Hz, 1H), 5.78 (d, J=15.8 Hz, 1H), 5.66 (dt, J=6.0, 15.7 Hz,1H), 5.45 (m, 2H), 4.66 (m, 1H), 4.51 (m, 2H), 4.23 (m, 2H), 3.99 (m,1H), 3.83 (s, 3H), 3.66 (d, J=5.3 Hz, 2H), 3.29 (t, J=4.7 Hz, 1H), 2.79(m, 1H), 2.65 (m, 1H), 2.49 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.33(t, J=7.1 Hz, 3H), 1.12 (d, J=6.7 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 1.06(d, J=6.9 Hz, 3H), 1.01 (s, 9H), 1.00 (s, 9H), 0.20 (s, 3H), 0.19 (s,3H), 0.17 (s, 3H), 0.15 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 158.9,152.2, 144.3, 134.3, 133.9, 131.0, 130.5, 129.3, 128.6, 127.6, 126.7,126.4, 120.2, 113.5, 107.0, 86.6, 85.5, 73.4, 72.8, 66.3, 65.1, 59.9,55.1, 42.2, 38.9, 35.2, 26.0, 25.9, 18.2, 18.1, 14.6, 14.2, 13.7, −3.0,−4.1, −4.2, −4.3; HRMS (ESI) calcd for C₅₉H₈₄O₇Si₂K 999.5393 (M+K)⁺,found 999.5387; [α]²⁰ _(D) +4.6 (c 3.1, CHCl₃).

9(S),11(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-5(R)-(4-methoxy-benzyloxy)-4(S),6(S),12(R)-trimethyl-15-trityloxy-pentadeca-7,13-dienoicacid ethyl ester (66). To a stirred solution of unsaturated ester 65(2.02 g, 2.10 □mol) in MeOH (10 ml), THF (1 ml) at 0° C. was added 0.25g of NiCl₂6H₂O then portionwise NaBH₄ (0.16 g). After 1 h, the reactionmixture was evaporated and filtered with Celite using Et₂O as an eluent(5 ml). The organic phase was concentrated and the residue was purifiedby flash chromatography (EtOAc/Hexane 1:9) to yield 1.96 g (2.04 μmol)of product 66 (97%) as a colorless oil: IR (CHCl₃) 2956, 2929, 2856,1735, 1613, 1514, 1479, 1448, 1374, 1249, 1174, 1072, 836, 773, 706cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.53 (m, 6H), 7.33 (m, 1H), 6.84 (m,2H), 5.81 (dd, J=15.7, 6.1 Hz, 1H), 5.65 (m, 1H), 5.45 (m, 2H), 4.65 (m,1H), 4.56 (d, J=10.9 Hz, 1H), 4.45 (d, J=10.9 Hz, 1H), 4.14 (q, J=7.1Hz, 2H), 3.96 (m, 1H), 3.80 (s, 3H), 3.62 (m, 2H), 3.14 (m, 1H), 2.79(m, 1H), 2.43 (m, 1H), 2.23 (m, 1H), 1.72 (m, 2H), 1.54 (m, 3H), 1.28(t, J=7.1 Hz, 3H), 1.06 (d, J=6.7 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.97(s, 18H), 0.93 (d, J=6.4 Hz, 3H), 0.17 (s, 3H), 0.154 (s, 3H), 0.151 (s,3H), 0.14 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.6, 158.8, 144.4, 134.6,133.6, 132.1, 131.2, 129.1, 128.7, 127.7, 126.8, 126.4, 103.4, 86.6,86.1, 73.8, 72.8, 66.5, 65.2, 60.0, 55.1, 42.8, 42.3, 35.4, 35.1, 32.3,29.4, 26.0, 25.9, 18.4, 18.1, 14.6, 14.2, 13.9, −2.9, −4.0, −4.1; HRMS(ESI) calcd for C₅₉H₈₆O₇Si₂K 1001.5549 (M+K)⁺, found 1001.5586; [α]²⁰_(D) −9.8 (c 0.95, CHCl₃).

4(R)-Benzyl-3-[9(S),11(S)-bis-(tert-butyl-dimethyl-silanyloxy)-5(R)-(4-methoxy-benzyloxy)-4(R),6(S),12(S)-trimethyl-15-trityloxy-pentadeca-7,13-dienoyl]-oxazolidin-2-one(68). To the stirred solution of ester 66 (1.61 g, 1.670 mol) in EtOH(20 ml), THF (2 ml) was added 1N aqueous KOH solution (17 ml) and themixture was refluxed gently until the ester disappeared (about 6 h) asdetermined by TLC. The ethanolic solution was concentrated and thendiluted with EtOAc (20 ml). After the solution was acidified to pH3 with1N HCl solution, organic phase was separated and aqueous phase wasextracted with EtOAc (2×10 ml). The combined organic phase were driedwith MgSO₄, concentrated and used as crude without further purification.A solution of the above acid and Et₃N (0.47 ml) in dry THF (17 ml) wascooled to −78° C., treated dropwise with pivaloyl chloride (0.25 ml),stirred in the cold for 1 h, and warmed to 0° C. prior to the additionof the (S)-oxazolidinone 4 (0.30 g) and LiCl (0.21 g). This reactionmixture was stirred overnight at room temperature and diluted with water(10 ml). The separated aqueous phase was extracted with ether (2×10 ml)and the combined organic phase were dried and evaporated and flashcolumn chromatography (EtOAc/hexane 1:4) gave the product 68 (1.52 g,83%) as a colorless oil: IR (CHCl₃) 2956, 2856, 1785, 1701, 1612, 1513,1449, 1385, 1249, 1074, 910, 836, 774, 734, 706 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 7.47 (m, 6H), 7.30 (m, 10H), 7.24 (m, 6H), 6.78 (m, 2H), 5.75(dd, J=15.7, 6.2 Hz, 1H), 5.54 (dt, J=15.5, 5.5 Hz, 1H), 5.41 (m, 2H),4.62 (m, 2H), 4.55 (d, J=11.0 Hz, 1H), 4.42 (d, J=11.1 Hz, 1H), 4.16 (m,2H), 3.91 (m, 1H), 3.75 (s, 3H), 3.56 (m 2H), 3.30 (dd, J=13.4, 3.2 Hz,1H), 3.15 (dd, J=6.7, 2.2 Hz, 1H), 2.85 (m, 2H), 2.77 (m, 2H), 2.37 (m,1H), 1.78 (m, 2H), 1.61 (m, 3H), 1.44 (m, 3H), 1.01 (d, J=6.7 Hz, 3H),0.96 (d, J=7.1 Hz, 3H), 0.92 (m, 21H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09(s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 173.1, 158.7, 153.2, 144.3, 135.3,134.7, 133.6, 132.5, 131.2, 129.3, 129.1, 128.8, 128.6, 127.6, 127.2,126.7, 126.2, 113.4, 86.5, 85.8, 73.7, 72.7, 66.4, 65.9, 65.1, 55.0,42.8, 42.4, 37.8, 35.5, 34.9, 33.5, 28.7, 26.0, 25.9, 18.2, 18.1, 14.5,13.9, −2.9, −4.0, −4.2; HRMS (ESI) calcd for C₆₇H₉₁NO₈Si₂K 1132.5920(M+K)⁺, found 1132.5874; [α]²⁰ _(D) +14.8 (c 0.61, CHCl₃).

4(R)-Benzyl-3-[9(S),11(S)-bis-(tert-butyl-dimethyl-silanyloxy)-5(R)-(4-methoxy-benzyloxy)-2(S),4(S),6(S),12(R)-tetramethyl-15-trityloxy-pentadeca-7,13-dienoyl]-oxazolidin-2-one(69). NaHMDS (1.0 M in THF, 1.68 ml) was added at −78° C. to a solutionof 68 (1.67 g) in THF (4 ml). After 30 min, the reaction mixture wastreated with MeI (0.29 ml) at −78° C., stirred for an additional 4 h,quenched with sat'd aqueous NH₄Cl, and extracted with ether (2×10 ml).The combined organic layers were dried (MgSO₄), concentrated andpurified by flash column chromatography (EtOAc/hexane 1:9) to giveproduct 69 (1.05 g, 62%) as a colorless oil: IR (CHCl₃) 2957, 2929,2856, 1783, 1697, 1513, 1449, 1385, 1249, 1074, 836, 774, 705 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.49 (m, 6H), 7.29 (m, 16H), 6.80 (m, 2H), 5.79(dd, J=15.6, 6.2 Hz, 1H), 5.56 (dt, J=15.6, 5.7 Hz, 1H), 5.42 (m, 2H),4.62 (m, 2H), 4.56 (d, J=11.3 Hz, 1H), 4.37 (d, J=11.1 Hz, 1H), 4.17 (m,1H), 4.05 (m, 1H), 3.92 (m, 1H), 3.77 (s, 3H), 3.58 (d, J=5.2 Hz, 1H),3.27 (m, 1H), 3.08 (dd, J=6.3, 2.5 Hz, 1H), 2.77 (m, 2H), 2.38 (m, 1H),1.76 (m, 1H), 1.64 (m, 2H), 1.46 (m, 4H), 1.10 (d, J=6.7 Hz, 3H), 1.00(d, J=6.3 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H), 0.93 (m, 21H), 0.14 (s, 3H),0.11 (s, 6H), 0.10 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.3, 158.7,152.8, 144.4, 135.3, 134.9, 133.6, 132.3, 131.3, 129.4, 128.9, 128.8,128.6, 127.6, 127.2, 126.7, 126.3, 113.5, 86.6, 86.5, 74.0, 72.8, 66.5,65.8, 65.2, 43.0, 42.5, 37.8, 35.4, 35.3, 33.0, 26.3, 26.0, 25.9, 18.3,18.1, 17.4, 14.5, 14.2, −2.9, −4.0, −4.1, −4.2; HRMS (ESI) calcd forC₆₈H₉₃NO₈Si₂K 1146.6077 (M+K)⁺, found 1146.6079; [α]²⁰ _(D) +16.70 (c1.1, CHCl₃).

9(S),11(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-5(R)-(4-methoxy-benzyloxy)-2(S),4(S),6(S),12(R)-tetramethyl-15-trityloxy-pentadeca-7,13-dien-1-ol(70). To a stirred solution of 69 (0.41 g, 0.37 mmol) in THF (1.5 ml) at0° C. was added MeOH (0.015 ml) and LiBH₄ (0.81 ml, 2.0 M soln in THF)dropwise. After stirring 2 h at 0° C., saturated sodium potassiumtartrate (10 ml) was added dropwise. The reaction mixture was warmed toroom temperature and extracted with CH₂Cl₂ (10 ml×2). The combinedorganic layer were washed with brine (10 ml) and dried over anhydrousMgSO₄, evaporated and the residue was chromatographed (hexane/EtOAc 4:1)to yield 70 (0.30 g, 87%) as a colorless oil: IR (CHCl₃) 3400, 2956,2928, 2856, 1613, 1514, 1449, 1377, 1249, 1074, 836, 774, 706 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 7.48 (m, 6H), 7.29 (m, 11H), 6.84 (m, 2H), 5.78(dd, J=15.7, 6.0 Hz, 1H), 5.58 (dt, J=15.7, 5.2 Hz, 1H), 5.46 (m, 1H),5.35 (m, 1H), 4.59 (t, J=9.5, Hz, 1H), 4.48 (q, J=10.9 Hz, 2H), 3.92 (m,1H), 3.79 (s, 3H), 3.57 (d, J=5.5 Hz, 2H), 3.25 (m 2H), 3.03 (t, J=4.5Hz, 1H), 2.75 (m 1H), 2.41 (m, 1H), 1.75 (m, 1H), 1.55 (m, 2H), 1.32 (m,2H), 1.17 (m, 2H), 1.07 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.94(s, 9H), 0.91 (m, 12H), 0.72 (d, J=6.6 Hz, 3H), 0.13 (s, 3H), 0.12 (s,3H), 0.09 (s, 3H), 0.07 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 158.9, 144.4,134.4, 133.4, 131.5, 131.4, 129.1, 128.7, 127.7, 126.8, 126.5, 113.6,87.6, 86.8, 74.1, 73.0, 68.9, 66.5, 65.4, 55.2, 42.7, 42.4, 37.1, 35.0,33.1, 26.0, 25.9, 18.9, 18.1, 15.8, 14.9, 14.7, −2.8, −4.0, −4.06,−4.10; HRMS (ESI) calcd for C₅₈H₈₆O₆Si₂K 973.6301 (M+K)⁺, found973.6264; [α]²⁰ _(D) −31.7 (c 1.3, CHCl₃).

{3(R)-[2-(4-Methoxy-phenyl)-5(S)-methyl-[1(S),3]dioxan-4-yl]-2-oxo-butyl}-phosphonicacid dimethyl ester (71). n-Butyllithium (4.5 ml, 1.6 M solution inhexane) was added dropwise to a stirred solution of dimethylmethanephosphonate (0.77 ml) in THF (7 ml) at −78° C. After 1 h, asolution of the known weinreb amide (Smith, A. B. et al. J. Am. Chem.Soc. 2000, 122, 8654–8664) (0.46 g) in THF (0.5 ml) was added. After 30min, the reaction was then allowed to warm to 0° C. and quenched bypouring into brine (100 ml) and extracted with EtOAc (2×50 ml). Thecombined extracts were washed with brine (50 ml), dried over MgSO₄ andconcentrated in vacuo. Flash silica gel column chromatography (EtOAc)gave the desired product 71 (0.47 g, 85%) as a colorless oil: ¹H NMR(300 MHz, CDCl₃) δ 7.38 (m, 2H), 6.89 (m, 2H), 5.50 (s, 1H), 4.14 (dd,J=11.3, 4.7, Hz, 1H), 4.06 (dd, J=10.0, 2.7 Hz, 1H), 3.80 (s, 3H), 3.77(s, 3H), 3.74 (s, 3H), 3.59 (t, J=11.1 Hz, 1H), 3.42 (d, J=14.5 Hz, 1H),3.34 (d, J=14.5 Hz, 1H), 3.20 (d, J=14.5 Hz, 1H), 3.13 (d, J=14.5 Hz,1H), 3.02 (dq, J=2.8, 7.0 Hz, 1H), 2.06 (m, 1H), 1.26 (d, J=7.0 Hz, 3H),0.85 (d, J=6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 202.5, 159.5, 130.4,126.9, 113.1, 100.5, 82.1, 72.4, 54.9, 52.6, 48.6, 39.3, 37.6, 30.6,11.6, 8.7

13(S),15(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-2-[2-(4-methoxy-benzyl)-5(S)-methyl-[1,3(S)]dioxan-4-yl]-9(R)-(4-methoxy-benzyloxy)-6(S),8(S),10(S),16(R)-tetramethyl-19-trityloxy-nonadeca-4,11,17-trien-3-one(72). The alcohol 70 (0.30 g, 0.32 μmol) in CH₂Cl₂ (10 mL) was treatedwith Dess-Martin periodinane (0.20 g, 0.47 μmol). After 1 h, the mixturewas quenched with saturated NaHCO₃ (10 mL). The aqueous layer wasextracted with ethyl ether (10 mL×2) and the combined extracts weredried over anhydrous MgSO₄. Filtration and concentration followed byshort flash column chromatography filtration (hexane/EtOAc 4:1) toremove the residue from Dess-Martin reagent provided crude aldehyde as acolorless oil which was used for the next reaction without furtherpurification. A mixture of ketophosphonate 71 (0.14 g) and Ba(OH)₂(0.043 g, activated by heating to 100° C. for 1˜2 h before use) in THF(2 ml) was stirred at room temperature for 30 min. A solution of theabove aldehyde in wet THF (2 ml+2×1 ml washings, 40:1 THF/H₂O) was thenadded and stirred for overnight. The reaction mixture was diluted withEt₂O (10 ml) and washed with sat'd NaHCO₃ (10 ml) and brine (10 ml). Theorganic solution was dried (MgSO₄) and the solvent was evaporated invacuo. The residue was chromatographed (hexane/EtOAc 4.5:1) to yield 72(0.34 g, 90%) as a colorless oil: IR (CHCl₃) 2957, 2929, 2855, 1615,1515, 1461, 1249, 1076, 1036, 835, 774 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ7.47 (m, 6H), 7.38 (m, 2H), 7.28 (m, 12H), 6.89 (m, 2H), 6.78 (m, 2H),6.22 (d, J=15.6 Hz, 1H), 5.74 (dd, J=15.7, 6.2 Hz, 1H), 5.57 (m, 1H),5.45 (s, 1H), 5.38 (m, 2H), 4.60 (m, 1H), 4.52 (d, J=11.0 Hz, 1H), 4.33(d, J=11.0 Hz, 1H), 4.12 (dd, J=11.2, 4.5 Hz, 1H), 3.90 (m, 2H), 3.81(s, 3H), 3.76 (s, 3H), 3.55 (m, 3H), 3.04 (m, 1H), 2.92 (m, 1H), 2.75(m, 1H), 2.36 (m, 1H), 2.25 (quint, J=7.2 Hz, 1H), 2.02 (m, 1H), 1.71(m, 1H), 1.56˜1.33 (m, 4H), 1.25 (d, J=6.9 Hz, 3H), 0.96 (d, J=7.8 Hz,3H), 0.95 (d, J=7.1 Hz, 3H), 0.92 (m, 21H), 0.85 (d, J=7.3 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 201.1, 159.7, 158.8, 153.1, 144.3, 134.6, 133.6,132.4, 131.2, 131.0, 129.1, 128.6, 127.7, 127.2, 126.8, 126.3, 126.0,113.5, 113.4, 100.7, 86.6, 85.7, 82.8, 73.8, 72.8, 66.4, 65.2, 55.2,47.0, 42.8, 42.4, 40.4, 35.5, 34.2, 32.8, 32.2, 26.0, 25.9, 19.2, 18.4,18.3, 18.1, 14.5, 14.4, 12.4, 10.7, −2.9, −4.0, −4.1; HRMS (ESI) calcdfor C₇₄H₁₀₄O₉Si₂K 1231.6856 (M+K)⁺, found 1231.6850; [α]²⁰ _(D) +22.8 (c0.88, CHCl₃).

13(S),15(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-2-[2-(4-methoxy-benzyl)-5(S)-methyl-[1,3(S)]dioxan-4-yl]-9(R)-(4-methoxy-benzyloxy)-6(S),8(S),10(S),16(R)-tetramethyl-19-trityloxy-nonadeca-11,17-dien-3-one(73). To a stirred solution of unsaturated ketone 72 (0.34 g, 0.29 mmol)in MeOH (4 ml), THF (0.5 ml) at 0° C. was added 0.034 g of NiCl₂.6H₂Othen portionwise NaBH₄ (0.022 g). After 1 h, the reaction mixture wasevaporated and filtered with Celite using Et₂O as a eluent (5 ml). Theorganic phase was concentrated and the residue was purified by flashchromatography (EtOAc/Hexane 1:4) to yield 0.31 g of product 73 (89%) asa colorless oil: IR (CHCl₃) 2956, 2929, 2855, 1713, 1614, 1515, 1461,1249, 1075, 1036, 835, 774, 706 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.47 (m,6H), 7.29 (m, 13H), 6.87 (m, 2H), 6.80 (m, 2H), 5.75 (dd, J=15.7, 6.1Hz, 1H), 5.55 (m, 1H), 5.45 (s, 1H), 5.38 (m, 2H), 4.60 (m, 1H), 4.48(d, J=10.9 Hz, 1H), 4.36 (d, J=10.9 Hz, 1H), 4.13 (dd, J=11.2, 4.4 Hz,1H), 3.93 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.55 (m, 2H), 2.99 (m,2H), 2.70 (m, 2H), 2.45 (t, J=7.0 Hz, 1H), 2.36 (m, 1H), 2.02 (m, 1H),1.75 (m, 1H), 1.63 (m, 1H), 1.49 (m, 2H), 1.37 (m, 3H), 1.23 (d, J=7.1Hz, 3H), 1.02 (d, J=6.7 Hz, 3H), 0.95 (d, J=7.0 Hz, 3H), 0.91 (m, 211H),0.81 (d, J=6.8 Hz, 3H), 0.80 (d, J=6.7 Hz, 3H), 0.12 (s, 3H), 0.09 (s,6H), 0.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 211.9, 159.8, 158.8, 144.6,144.4, 134.9, 133.4, 132.3, 131.8, 131.5, 131.0, 129.0, 128.9, 128.7,127.7, 127.6, 127.2, 126.8, 126.7, 126.3, 113.5, 100.8, 87.4, 86.7,83.1, 74.0, 72.9, 66.6, 65.2, 55.22, 55.18, 48.3, 43.1, 42.5, 41.6,38.3, 35.5, 32.7, 31.5, 31.3, 29.6, 26.1, 26.0, 19.0, 18.5, 18.1, 14.5,14.1, 12.1, 9.7, −2.9, −4.0, −4.1, −4.2; HRMS (ESI) calcd forC₇₄H₁₀₈O₉Si₂K 1233.7013 (M+K)⁺, found 1233.7036; [α]²⁰ _(D) +3.0 (c 1.7,CHCl₃).

13(S),15(S)-Bis-(tert-butyl-dimethyl-silanyloxy)-2-[2-(4-methoxy-benzyl)-5(S)-methyl-[1,3(S)]dioxan-4-yl]-9(R)-(4-methoxy-benzyloxy)-6(S),8(S),10(S),16(R)-tetramethyl-19-trityloxy-nonadeca-11,17-dien-3-ol(74). To a solution of 73 (0.27 g) in MeOH (4 ml) was added NaBH₄ (0.013g) at 0° C. After stirring for 2 h at 0° C., the reaction mixture wasevaporated and water (5 ml) was added. The reaction mixture wasextracted with ether (2×20 ml) and washed with brine (10 ml), dried overMgSO₄ and concentrated in vacuo. The residue was purified by flashchromatography (EtOAc/Hexane 1:4.5) to yield 0.19 g of major product 74(71%) and 0.069 g (25%) of minor product as a colorless oil: (majorisomer) IR (CHCl₃) 3533, 2956, 2929, 2855, 1614, 1515, 1462, 1250, 1072,1036, 835, 774, 734 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.51 (m, 6H), 7.43(m, 2H), 7.30 (m, 1H), 6.92 (m, 2H), 6.84 (m, 2H), 5.78 (dd, J=15.6, 6.1Hz, 1H), 5.61 (m, 1H), 5.57 (s, 1H), 5.43 (m, 2H), 4.65 (m, 1H), 4.55(d, J=11.0 Hz, 1H), 4.45 (d, J=10.8 Hz, 1H), 4.18 (dd, J=11.2, 4.5 Hz,1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.82 (m, 1H), 3.79 (s, 3H), 3.74 (m,1H), 3.59 (m, 2H), 3.06 (m, 2H), 2.78 (m, 1H), 2.41 (m, 1H), 2.19 (m,1H), 1.81 (m, 2H), 1.56 (dd, J=13.8, 8.1 Hz, 3H), 1.44 (m, 3H), 1.34 (m,3H), 1.08 (d, J=7.0 Hz, 6H), 0.99 (d, J=7.2 Hz, 3H), 0.96 (m, 18H), 0.90(d, J=6.7 Hz, 3H), 0.82 (d, J=6.6 Hz, 6H), 0.16 (s, 3H), 0.14 (s, 6H),0.13 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 160.0, 158.8, 144.6, 144.4,134.9, 133.4, 132.3, 131.5, 130.7, 129.0, 128.9, 128.7, 127.7, 127.6,127.2, 126.8, 126.7, 126.3, 113.7, 113.5, 89.0, 87.5, 86.7, 76.7, 74.0,73.1, 72.8, 66.6, 65.2, 55.2, 55.1, 43.1, 42.5, 41.8, 37.4, 35.5, 34.4,32.9, 32.4, 30.4, 30.1, 26.0, 25.9, 19.2, 18.5, 18.1, 14.5, 14.1, 11.9,5.7, −2.9, −4.0, −4.1, −4.2; HRMS (ESI) calcd for C₇₄H₁₀₈O₉Si₂K1235.7169 (M+K)⁺, found 1235.7149; [α]²⁰ _(D) +3.5 (c 0.6, CHCl₃).

5,15(S),17(S)-Tris-(tert-butyl-dimethyl-silanyloxy)-11(R)-(4-methoxy-benzyloxy)-3(S)-[2-(4-methoxy-phenyl)-ethoxy]-2(S),4(R),8(S),10(S),12(S),18(R)-hexamethyl-21-trityloxy-heneicosa-13,19-dien-1-ol(76). To a stirred solution of 74 (0.19 g, 0.16 mmol) and 2,6-lutidine(0.037 mL, 0.32 mmol) in CH₂Cl₂ (16 mL) at 0° C. was added TBDMSOTf(0.055 mL, 0.24 mmol) and the reaction mixture was stirred for 2 h atambient temperature. The reaction mixture was quenched by the additionof water (5 mL). The reaction mixture was extracted by CH₂Cl₂ and driedover MgSO₄ followed by the evaporation of the solution under reducedpressure. The residue was purified by short column chromatography(hexane/EtOAc 9:1). To a stirred solution of TBS protected acetal (0.20g, 0.15 mmol) in anhydrous CH₂Cl₂ (3 mL), under an atmosphere of N₂ at0° C. was added diisobutylaluminum hydride (1.0 M in THF, 1.5 mL, 1.5mmol) dropwise, and the reaction mixture was stirred for additional 1 hat 0° C. The reaction mixture was quenched by the careful addition ofaqueous sat'd potassium sodium tartrate solution (10 mL). The reactionmixture was stirred for 3 h at room temperature. The organic layer wasseparated, and the water layer was extracted by CH₂Cl₂ (20 mL). Thecombined organic layer was washed with brine and dried over MgSO₄followed by the evaporation of the organic solution under reducedpressure. The residue was purified by column chromatography(EtOAc/hexane 1:4) whereupon the pure compound 76 (0.19 g, 91% for 2steps) was obtained: IR (CHCl₃) 3466, 2955, 2928, 26, 1613, 1514, 1462,1249, 1072, 1037, 835, 773 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.52 (m, 6H),7.30 (m, 13H), 6.94 (m, 2H), 6.85 (m, 2H), 5.79 (dd, J=15.7, 6.3 Hz,1H), 5.59 (dt, J=15.7, 5.9 Hz, 1H), 5.44 (m, 2H), 4.67 (m, 1H), 4.60 (s,2H), 4.57 (d, J=11.1 Hz, 1H), 4.44 (d, J=10.9 Hz, 1H), 3.97 (m, 1H),3.91 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.68 (m, 2H), 3.60 (d, J=5.6Hz, 1H), 3.52 (dd, J=6.6, 4.3 Hz, 1H), 3.07 (m, 2H), 2.97 (brs, 1H),2.80 (dd, J=14.5, 6.7 Hz, 1H), 2.40 (m, 1H), 2.02 (m, 1H), 1.95 (ddd,J=9.6, 6.9, 4.0 Hz, 1H), 1.81 (m, 1H), 1.71 (m, 1H), 1.56 (m, 3H), 1.47(m, 3H), 1.33 (m, 2H), 1.19 (d, J=7.0 Hz, 3H), 1.08 (d, J=6.7 Hz, 6H),1.00 (s, 9H), 0.97 (m, 21H), 0.90 (d, J=6.7 Hz, 3H), 0.82 (d, J=6.4 Hz,3H), 0.17 (s, 3H), 0.15 (s, 3H), 0.14 (s, 3H), 0.137 (s, 3H), 0.133 (s,3H), 0.127 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 159.3, 158.8, 144.6,144.4, 135.0, 133.6, 132.5, 131.4, 130.6, 129.2, 129.0, 128.9, 128.7,127.7, 127.6, 126.8, 126.7, 126.3, 113.9, 113.5, 87.4, 86.7, 85.9, 75.3,74.0, 73.6, 72.8, 66.6, 65.2, 65.1, 55.2, 55.1, 43.2, 42.5, 42.0, 41.5,37.0, 35.6, 33.4, 32.9, 31.9, 30.1, 26.08, 26.05, 25.98, 19.4, 18.4,18.1, 15.8, 14.4, 13.9, 10.0, −2.9, −3.7, −3.9, −4.1, −4.2, −4.4; HRMS(ESI) calcd for C₈₀H₁₂₄O₉Si₃K 1351.8190 (M+K)⁺, found 1351.8134; [α]²⁰_(D) −6.1 (c 0.48, CHCl₃).

7,17(S),19(S)-Tris-(tert-butyl-dimethyl-silanyloxy)-5(S),13(R)-bis-(4-methoxy-benzyloxy)-4(S),6(S),10(R),12(S),14(S),20(S)-hexamethyl-23-trityloxy-tetracosa-1,3,15,21-tetraen(77). The alcohol 76 (0.17 g, 0.13 μmol) in CH₂Cl₂ (5 ml) was treatedwith Dess-Martin periodinane (0.081 g, 0.2 μmol). After 1 h, the mixturewas quenched with saturated NaHCO₃ (5 ml). The aqueous layer wasextracted with ethyl ether (5 ml×2) and the combined extracts were driedover anhydrous MgSO₄. Filtration and concentration followed by shortflash column chromatography filtration (hexane/EtOAc 4.5:1) to removethe residue from Dess-Martin reagent provided crude aldehyde as acolorless oil which was used for the next reaction without furtherpurification. To a stirred solution of the above crude aldehyde and1-bromoallyl trimethylsilane (160 mg, 0.65 mmol) in anhydrous THF (3 ml)under an atmosphere of N₂ at room temperature was added CrCl₂ (0.13 g,1.1 mmol) and the mixture was stirred for additional 14 h at ambienttemperature. The reaction mixture was diluted with hexane followed byfiltration through celite. After the evaporation of the solvent underreduced pressure, the residue was purified by short silica gel columnchromatography using EtOAc/hexane (1:9). The foregoing product in THF (3ml) was cooled to 0° C. and NaH (95% w/w, 64 mg, 2.56 mmol) was added inone portion. The ice bath was removed after 15 min and the mixture wasstirred for 2 h at ambient temperature. The reaction mixture was cooledto 0° C., quenched with H₂O (5 ml), extracted with ethyl ether (5 ml×2).The combined organic layer was washed with brine and dried over MgSO₄followed by the evaporation of the organic solution under reducedpressure. The residue was purified by column chromatography(hexane/EtOAc 9:1) whereupon the pure compound 77 (122 mg, 72% for 3steps) was obtained: IR (CHCl₃) 2955, 2928, 2856, 1613, 1514, 1462,1249, 1072, 1039, 835, 773, 705 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.47 (m,6H), 7.28 (m, 13H), 6.89 (m, 2H), 6.79 (m, 2H), 6.61 (ddd, J=16.8, 10.7,10.6 Hz, 1H), 6.04 (t, J=10.8 Hz, 1H), 5.73 (dd, J=15.6, 6.3 Hz, 1H),5.61 (t, J=10.4 Hz, 1H), 5.58 (m, 1H), 5.37 (m, 2H), 5.20 (d, J=16.8 Hz,1H), 5.11 (d, J=10.1 Hz, 1H), 4.54 (m, 31H), 4.50 (d, J=11.0 Hz, 1H),4.37 (d, J=10.8 Hz, 1H), 3.90 (m, 1H), 3.82 (s, 31H), 3.76 (s, 3H), 3.62(m, 1H), 3.54 (d, J=5.3 Hz, 1H), 3.35 (dd, J=7.7, 3.1 Hz, 1H), 3.00 (m,2H), 2.73 (m, 1H), 2.31 (m, 1H), 1.69 (m, 4H), 1.43 (m, 8H), 1.14 (d,J=6.8 Hz, 3H), 1.00 (d, J=7.1 Hz, 3H), 0.96 (s, 9H), 0.92 (s, 3H), 0.91(s, 3H), 0.89 (m, 6H), 0.83 (d, J=6.6 Hz, 3H), 0.72 (d, J=6.4 Hz, 3H),0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 159.0, 158.8, 144.6, 144.4, 135.0, 134.6, 133.7, 133.4, 132.6,132.4, 131.5, 131.4, 129.1, 129.0, 128.98, 128.94, 128.7, 127.7, 126.8,126.3, 117.2, 113.7, 113.5, 87.3, 86.7, 84.3, 75.0, 74.0, 72.9, 72.8,66.6, 65.2, 55.2, 55.1, 43.2, 42.6, 42.0, 40.6, 35.7, 35.3, 33.2, 32.8,32.3, 30.1, 26.1, 26.0, 19.4, 18.8, 18.3, 18.2, 18.1, 14.4, 14.0, 13.9,−2.9, −3.6, −3.9, −4.1, −4.2, −4.4; [α]²⁰ _(D) +2.5 (c 1.2, CHCl₃).

7(S),9(S),19-Tris-(tert-butyl-dimethyl-silanyloxy)-13(R),21(S)-bis-(4-methoxy-benzyloxy)-6(R),12(S),14(S),16(S),20(R),22(S)-hexamethyl-hexacosa-2,4,10,23,25-pentaenoicacid methyl ester (79). A solution of 77 (18.6 mg) in CH₂Cl₂ (0.2 ml)was cooled to −78° C. and B-chlorocatecholborane (0.25 M in CH₂Cl₂, 0.17ml) was added. The solution was stirred at −78° C. for 1 h followed bytreatment with sat'd aqueous NaHCO₃ (1 ml). The resulting reactionmixture was then diluted with CH₂Cl₂ (10 ml) and H₂O (3 ml). The layerswere separated and the aqueous layer was further extracted with CH₂Cl₂(2×5 ml). The combined organic layers were washed with brine, dried overMgSO₄ and concentrated under vacuum. The residue was purified by flashchromatography (hexane/EtOAc 4;1) on silica gel to yield 78 (9.4 mg) asa colorless oil. The alcohol 78 (20 mg, 0.018 μmol) in CH₂Cl₂ (0.5 mL)was treated with Dess-Martin periodinane (12 mg, 0.028 mmol). After 1 h,the mixture was quenched with saturated NaHCO₃ (1 ml). The aqueous layerwas extracted with ethyl ether (3 ml×2) and the combined extracts weredried over anhydrous MgSO₄. Filtration and concentration followed byshort flash column chromatography filtration (hexane/EtOAc 4.5:1) toremove the residue from Dess-Martin reagent provided crude aldehyde as acolorless oil which was used for the next reaction without furtherpurification. To a stirred solution ofbis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl) phosphate (0.005 ml,0.024 □mol), 18-crown-6 (0.024 g, 0.09 mmol) in THF (0.5 ml) cooled to−78° C. was added dropwise potassium bis(trimethylsilyl)amide (0.044 ml,0.022 □mol, 0.5M solution in toluene). Thereafter the above aldehyde inTHF (0.5 ml) was added and the solution was stirred for 6 h at −78° C.The reaction mixture was quenched by addition of a sat'd NH₄Cl solution(1 ml) and diluted with diethyl ether (5 ml). The layers were separatedand organic phase was washed with brine (5 ml) and dried with MgSO₄,filtered, and concentrated. The residue was purified by flashchromatography (EtOAc/Hexane 1:9) yielding 17 mg of (E,Z)-doublyunsaturated ester 79 (82% for 2 steps): IR (CHCl₃) 2956, 2929, 2856,1720, 1613, 1514, 1462, 1249, 1173, 1075, 836, 773 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 7.22 (m, 5H), 6.82 (m, 4H), 6.55 (ddd, J=16.8, 10.8, 10.8Hz, 1H), 6.38 (t, J=11.4 Hz, 1H), 6.05 (dd, J=15.4, 6.2 Hz, 1H), 5.98(t, J=11.0 Hz, 1H), 5.55 (t, J=10.5 Hz, 1H), 5.48 (d, J=11.5 Hz, 1H),5.31 (m, 2H), 5.14 (d, J=16.8 Hz, 1H), 5.05 (d, J=10.1 Hz, 1H), 4.54 (m,1H), 4.49 (m, 3H), 4.31 (d, J=10.9 Hz, 1H), 3.87 (m, 1H), 3.77 (s, 3H),3.75 (s, 3H), 3.68 (s, 3H), 3.57 (m, 1H), 3.29 (dd, J=7.7, 3.1 Hz, 1H),2.94 (m, 2H), 2.68 (m, 1H), 2.48 (m, 1H), 1.65 (m, 3H), 1.43–1.28 (m,6H), 1.20 (m, 2H), 1.08 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H), 0.94(d, J=6.1 Hz, 3H), 0.90 (s, 9H), 0.86 (m, 21H), 0.81 (d, J=6.7 Hz, 3H),0.71 (d, J=6.4 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02(s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 159.0, 158.8, 147.7, 146.9,145.8, 134.6, 133.5, 132.7, 132.5, 131.6, 131.4, 129.1, 128.9, 128.8,128.7, 128.4, 127.9, 127.7, 127.3, 126.4, 117.2, 114.9, 113.7, 113.6,87.6, 84.3, 77.2, 74.9, 74.2, 72.9, 72.7, 66.4, 55.3, 55.2, 50.9, 43.1,42.5, 42.1, 40.6, 35.8, 35.3, 33.6, 33.2, 32.9, 18.14, 18.11, 14.6,13.9, 9.3, −2.9, −3.6, −3.9, −4.1, −4.4; HRMS (ESI) calcd forC₆₇H₁₁₄O₉Si₃K 1185.7408 (M+K)⁺, found 1185.7464; [α]²⁰ _(D) −12.6 (c0.75, CHCl₃).

8(S),10(S),14(R),20-Tetrahydroxy-7(S),13(S),15(S),17(R),21(S)-pentamethyl-22(S)-(1(S)-methyl-penta-2,4-dienyl)-oxa-cyclodocosa-3,5,11-trien-2-one (83).The ester 79 (8.5 mg, 7.4 μmol) was dissolved in CH₂Cl₂ (1 ml)-H₂O (0.05ml) and DDQ (5.0 mg, 22 μmol) was added at 0° C. After 1 h of stirringat 0° C., the reaction mixture was quenched by adding sat'd NaHCO₃ (5ml). The organic phase was washed by sat'd NaHCO₃ solution (3×10 ml) andbrine, dried over MgSO₄ and concentrated. Purification by flash columnchromatography (EtOAc/hexane 1:4.5) furnished diol (6.4 mg, 95%) as acolorless oil. To the stirred solution of the above diol (6.4 mg, 7.06μmol) in EtOH (0.7 ml) was added 1N aqueous KOH solution (0.07 ml) andthe mixture was refluxed gently until the ester disappeared (about 7 h)as determined by TLC. The ethanolic solution was concentrated and thendiluted with ether (4 ml). After the solution was acidified to pH3 with1N HCl solution, organic phase was separated and aqueous phase wasextracted with EtOAc (2×2 ml). The combined organic phase were driedwith MgSO₄, concentrated and used as crude without further purification.A solution of above dihydroxy acid in THF (0.5 ml) was treated at 0° C.with Et₃N (0.006 ml, 43 μmol) and 2,4,6-trichlorobenzoyl chloride(0.0055 ml, 35 μmol). The reaction mixture was stirred at 0° C. for 30min and then added to a 4-DMAP (3.5 ml, 0.02 M solution in toluene) at25° C. and stirred for overnight. The reaction mixture was concentrated,EtOAc (5 mL) was added and the crude was washed with 1N HCl (2×5 ml),dried over MgSO₄. Purification by flash column chromatography(EtOAc/hexane 1:9) furnished macrolactone (3.0 mg, 49% for 2 steps) as acolorless oil. To a stirred solution of the above macrolactone (2.7 mg,3.1 μmol) in MeOH (0.5 ml) at 0° C. was added 0.5 ml of 3 N HCl(prepared by adding 25 ml of conc. HCl to 75 ml MeOH). After 2 h at roomtemperature, the reaction mixture was diluted with EtOAc (2 ml) and H₂O(2 ml) and the organic phase was separated and aqueous phase wasextracted with EtOAc (2×2 ml). The combined organic phase was washedwith sat'd NaHCO₃ (5 ml), dried with MgSO₄, concentrated and the residuewas purified by flash chromatography (EtOAc/Hexane 1:1) to yield 83 (1.2mg, 73%): IR (CHCl₃) 3400, 2960, 2926, 2854, 1693, 1635, 1599, 1461,1378, 1277, 1183, 1075, 964 cm⁻¹; ¹H NMR (500 MHz, CD₃OD) δ 7.34 (dd,J=15.3, 11.3 Hz, 1H), 6.64 (ddd, J=16.9, 10.5, 10.3 Hz, 1H), 6.57 (t,J=11.4 Hz, 1H), 5.96 (t, J=10.9 Hz, 1H), 5.95 (dd, J=15.3, 8.3 Hz, 1H),5.48 (t, J=10.0 Hz, 1H), 5.47 (d, J=11.6 Hz, 1H), 5.38 (dd, J=11.1, 8.9Hz, 1H), 5.27 (t, J=10.5 Hz, 1H), 5.16 (d, J=16.9 Hz, 1H), 5.08 (d,J=10.2 Hz, 1H), 5.02 (dd, J=8.0, 3.5 Hz, 1H), 4.65 (dt, J=3.1, 8.4 Hz,1H), 3.72 (ddd, J=9.0, 6.3, 2.8 Hz, 1H), 3.25 (ddd, J=10.2, 7.4, 2.8 Hz,1H), 3.16 (dd, J=5.4, 3.4 Hz, 1H), 3.06 (dd, J=16.3, 8.3 Hz, 1H), 2.72(ddd, J=10.2, 6.7, 6.6 Hz, 1H), 2.36 (dd, J=14.7, 7.2 Hz, 1H), 1.86 (dt,J=6.6, 3.1 Hz, 1H), 1.81 (ddd, J=10.5, 6.8, 3.7 Hz, 1H), 1.69 (m, 2H),1.58 (m, 1H), 1.47 (ddd, J=13.8, 9.5, 3.5 Hz, 1H), 1.37 (m, 1H), 1.25(m, 1H), 1.17 (m, 1H), 1.13 (m, 1H), 1.09 (d, J=6.8 Hz, 3H), 1.03 (d,J=6.9 Hz, 6H), 0.98 (d, J=6.7 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H), 0.76 (d,J=6.4 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.3, 147.2, 145.3, 134.39,134.37, 132.5, 132.3, 130.0, 127.6, 117.8, 116.5, 80.0, 75.4, 74.9,72.0, 66.2, 43.2, 41.5, 40.7, 40.6, 35.6, 35.4, 35.0, 33.0, 31.2, 30.4,20.4, 18.1, 17.3, 16.2, 12.4, 10.2; LRMS (ESI) calcd for C₃₂H₅₂O₆ 571.3(M+K)⁺, found 571.3; [α]²⁰ _(D) +32.6 (c 0.10, MeOH).

(Z)-(4R,5S,6S,7S)-tert-butyl-{6-(3, 4-dimethoxybenzyloxy)-4-[4-(4, 4, 5,5, 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11,11-heptadecafluoroundecyloxy)-benzyloxy]-5,7-dimethylundec-8-enyloxy}dimethylsilane (85). A mixture solution of 84(0.40 g, 0.39 mmol) in MeOH (8.0 ml) and CH₂Cl₂ (5.3 ml) was cooled to−78° C. and treated with a stream of ozone for 10 min. The reactionmixture was treated with dimethysulfide (2.0 ml) and pyridine (32 μl)and stirred for 3.0 h at ambient temperature. The reaction mixture wasconcentrated and diluted with Et₂O (80 ml). The organic layer was washedwith saturated aqueous CuSO₄ (2×20 ml) and brine (20 ml), dried overMgSO₄, filtered and concentrated. At ambient temperature, a suspensionof propyltriphenylphosphonium bromide (0.383 g 98% purity, 0.97 mmol) inTHF (15.0 ml) was added NaN(TMS)₂ (1.0 M solution in THF, 0.98 ml) atambient temperature. After stirring 1 h, this solution was cooled to−78° C. Then the crude residue in THF (2.0 ml) was introduced, and theresultant mixture was stirred for 3 h at −78° C. and was allowed to warmto ambient temperature for 12 h. The reaction mixture was quenched withsaturated aqueous NaHCO₃ (20 ml) and extracted with Et₂O (2×40 ml). Thecombined extracts were washed with brine (20 ml), dried over MgSO₄,filtered and concentrated. Flash chromatography (10% AcOEt/hexane)afforded 85 (0.08 g, 26% yield): ¹H-NMR (500 MHz, CDCl₃) δ 0.06 (s, 6H),0.91 (s, 9H), 0.93 (t, J=7.6 Hz, 3 H), 1.00 (d, J=6.8 Hz, 3H), 1.06 (d,J=6.8 Hz, 3H), 1.47 (m, 2H), 1.59 (m, 1H), 1.66 (m, 1 H), 1.83 (m, 1H),1.94 (m, 2H), 2.11 (m, 2H), 2.33 (m, 2H), 2.66 (m, 1H), 3.35 (m, 1H),3.60 (t, J=6.3 Hz, 2H), 3.88 (s, 6H), 4.04 (t, J=5.8 Hz, 2H), 4.38 (d,J=11.3 Hz, 1H), 4.48 (d, J=10.9 Hz, 1H), 4.53 (d, J=10.9 Hz, 1H), 4.59(d, J=11.3 Hz, 1H), 5.35 (dt, J=7.0, 10.3 Hz, 1H), 5.42 (dd, J=10.3,10.1 Hz, 1H), 6.82–7.02 (m, 4H), 7.21–7.28 (m, 2H); ¹³C NMR (125 MHz,CDCl₃) δ−5.2, 10.3, 14.5, 18.4, 18.9, 20.6, 20.9, 25.9, 26.9, 28.0 (t,J=22.5 Hz), 29.0, 34.9, 39.3, 55.8, 55.9, 63.2, 66.4, 70.8, 74.7, 79.4,84.2, 110.5, 110.9, 114.3, 119.9, 106–122 (m), 129.6, 131.1, 131.3,131.5, 131.6, 132.0, 148.4, 148.9, 158.2; IR (thin film/NaCl) cm⁻¹ 2933,2858, 1729, 1612, 1515, 1465, 1242, 1153, 1032, 834; MS (EI) m/z 1060(M⁺), 1035, 1003, 909, 567; [∝]_(D) ²⁰ +2.37° (c 0.590, CHCl₃).

(4R,5S,6S,7S)-tert-butyl-{6-(3, 4-dimethoxybenzyloxy)-4-[4-(4, 4, 5, 5,6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 13, 13,13-heneicosafluorotridecyloxy)benzyloxy]-5,7-dimethyl-non-8-enyloxy}dimethylsilane (84). A solution of the alcohol(0.26 g, 0.57 mmol) and1-bromomethyl-4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heneicosafluorotridecyloxy)benzene(0.50 g, 0.66 mmol) in THF (6.0 ml) was cooled to −40° C. and ^(t)BuOK(1.0 M solution in THF, 0.70 ml) was added. The reaction mixture wasstirred for 3.0 h. Then ^(t)BuOK (1.0 M solution in THF, 0.40 ml) wasadded again and the reaction solution was allowed to warm to ambienttemperature for 9 h. The reaction mixture was quenched with saturatedaqueous NaHCO₃ (20 ml) and extracted with Et₂O (2×40 ml). The combinedextracts were washed with brine (20 ml), dried over MgSO₄, filtered andconcentrated. Flash chromatography (10% AcOEt/hexane) afforded 84 (0.326g, 50% yield): ¹H-NMR (300 MHz, CDCl₃) δ 0.55 (s, 6H), 0.91 (s, 9H),1.06 (apparent d, J=6.8 Hz, 3H), 1.49 (m, 2H), 1.64 (m, 2H), 1.93 (m,1H), 2.07 (m, 2H), 2.21–2.48 (m, 3H), 3.38 (m, 2H), 3.61 (t, J=6.1 Hz,2H), 3.85 (s, 3H), 3.87 (s, 3H), 4.00 (t, J=5.7 Hz, 2H), 4.39 (d, J=11.2Hz, 1H), 4.47 (d, J=10.8 Hz, 1H), 4.49 (d, J=11.2 Hz, 1H), 4.56 (d,J=10.8 Hz, 1H), 5.00 (m, 2H), 5.92 (m, 1H), 6.79–6.91 (m, 4H), 7.27(apparent d, J=8.4 Hz, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 10.5, 14.0, 17.3,18.3, 20.6, 22.7, 25.9, 26.9, 28.0 (t, J=22.2 Hz), 29.0, 38.5, 42.1,55.7, 55.8, 63.1, 66.3, 70.9, 74.3, 79.9, 83.7, 110.9, 111.1, 114.3,114.6, 119.9, 105–124 (m), 129.5, 131.6, 131.9, 141.2, 148.5, 148.9,158.2; IR (thin film/NaCl) cm⁻¹ 2928, 2858, 1611, 1515, 1242, 1154; MS(EI) m/z 1132 (M⁺), 1075, 981, 817, 667, 465; [∝]_(D) ²⁰ +3.15° (c 1.11,CHCl₃).

(Z)-(4R,5S,6S,7S)-tert-Butyl-{6-(3, 4-dimethoxy-benzyloxy)-4-[4-(4, 4,5, 5, 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 13, 13,13-heneicosafluorotridecyloxy)benzyloxy]-9-iodo-5,7-dimethylnon-8-enyloxy}dimethylsilane(86). A mixture of 84 (0.326 g, 0.28 mmol) in MeOH (8.0 ml) and CH₂Cl₂(6.0 ml) was cooled to −78° C. and treated with a stream of ozone for 5min. The reaction mixture was treated with dimethylsulfide (1.5 ml) andpyridine (23 μl) and stirred for 3.0 h at ambient temperature. Thereaction mixture was concentrated and diluted with Et₂O (80 ml). Theorganic layer was washed with saturated aqueous CuSO₄ (2×20 ml) andbrine (20 ml), dried over MgSO₄, filtered and concentrated. At ambienttemperature, a suspension of (iodomethyl)triphenylphosphonium iodide(0.213 g, 0.40 mmol) in THF (3.0 ml) was added NaN(TMS)₂ (1.0 M solutionin THF, 0.40 ml). After stirring 0.5 h, this solution was cooled to −78°C. Then HMPA (0.13 ml) and the crude residue in THF (2.0 ml) wereintroduced, and the resultant mixture was stirred for 20 min at −78° C.and stirred at ambient temperature for 0.5 h. The reaction mixture wasquenched with saturated aqueous NaHCO₃ (20 ml) and extracted with Et₂O(2×40 ml). The combined extracts were washed with brine (20 ml), driedover MgSO₄, filtered and concentrated. Flash chromatography (10%AcOEt/hexane) afforded (Z)-(4R,5S,6S, 7S)-tert-butyl-{6-(3,4-dimethoxy-benzyloxy)-4-[4-(4, 4, 5, 5, 6, 6, 7, 7, 8, 8, 9, 9, 10, 10,11, 11, 12, 12, 13, 13,13-heneicosafluorotridecyloxy)benzyloxy]-9-iodo-5,7-dimethylnon-8-enyloxy}dimethylsilane(0.119 g, 33% yield): ¹H-NMR (300 MHz, CDCl₃) δ 0.04 (s, 6H), 0.89 (s,9H), 1.03 (d, J=6.9 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H), 1.23–1.77 (m, 5H),2.04 (m, 2H), 2.23 (m, 2H), 2.70 (m, 1H), 3.44 (m, 2H), 3.59 (t, J=6.3Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.03 (t, J=5.8 Hz, 2H), 4.40 (d,J=11.3 Hz, 1H), 4.53 (s, 2H), 4.57 (d, J=11.3 Hz, 1H), 6.15 (d, J=7.3Hz, 1H), 6.28 (dd, J=7.3, 9.0 Hz, 1H), 6.80–6.89 (m, 4H), 7.22–7.30 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ−5.2, 10.2, 14.2, 17.2, 18.4, 20.7, 22.8,26.0, 27.3, 28.0 (t, J=22.1 Hz), 29.8, 31.7, 40.2, 42.9, 51.4, 55.9,56.0, 63.3, 66.4, 71.1, 75.4, 78.9, 82.2, 84.1, 107–122 (m), 110.9,111.2, 114.4, 120.1, 129.5, 131.6, 131.8, 143.2, 148.6, 148.9, 158.2; IR(thin film/NaCl) cm⁻¹ 2956, 2859, 1727, 1611, 1514, 1467, 1243, 1154,856; MS (EI) m/z 1201 (M⁺−C₄H₉), 1107, 667; [∝]_(D) ²⁰ +4.04° (c 1.01,CHCl₃).

(Z)-(4R,5S,6S,7S)-tert-butyl-{6-(3,4-dimethoxybenzyloxy)-4-[4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heneicosafluorotridecyloxy)benzyloxy]-5,7-dimethyl-9-phenyl-non-8-enyloxy}dimethylsilane(87). To a solution of(Z)-(4R,5S,6S,7S)-tert-butyl-{6-(3,4-dimethoxy-benzyloxy)-4-[4-(4, 4, 5,5, 6, 6, 7, 7, 8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 13, 13,13-heneicosafluorotridecyloxy)benzyloxy]-9-iodo-5,7-dimethylnon-8-enyloxy}dimethylsilane(0.120 g, 0.09 mmol) and Pd(PPh₃)₄ (0.011 g, 0.01 mmol) in THF (1.0 ml)was added PhZnI (0.5 M solution in THF, 0.97 ml) at ambient temperature.After stirring for 24 h, the reaction mixture was quenched withsaturated aqueous NaHCO₃ (20 ml) and extracted with Et₂O (2×40 ml). Thecombined extracts were washed with brine (20 ml), dried over MgSO₄,filtered and concentrated. Flash chromatography (10% AcOEt/hexane)afforded 87 (0.0726 g, 63% yield): ¹H-NMR (300 MHz, CDCl₃) δ 0.09 (s,6H), 0.95 (s, 9H), 1.07 (d, J=6.8 Hz, 3H), 1.19 (d, J=6.7 Hz, 3H),1.27–1.59 (m, 4H), 1.85 (m, 1H), 2.13 (m, 21H), 2.35 (m, 2H), 3.11 (m,2H), 3.39 (brt, J=5.2 Hz, 1H), 3.57 (t, J=6.2 Hz, 2H), 3.84 (s, 3H),3.91 (s, 3H), 4.02 (d, J=11.3 Hz, 1H), 4.08 (t, J=5.8 Hz, 2H), 4.32 (d,J=11.3 Hz, 1H), 4.52 (d, J=10.6 Hz, 1H), 4.67 (d, J=10.6 Hz, 1H), 5.83,(dd, J=11.5, 11.5 Hz, 1H), 6.53 (d, J=11.5 Hz, 1H), 6.86–7.37 (m, 9H);¹³C NMR (75 MHz, CDCl₃) δ−5.2, 10.2, 14.2, 18.4, 18.9, 20.7, 22.8, 26.1,27.3, 27.8 (t, J=21.7 Hz), 28.9, 31.7, 35.6, 39.7, 55.8, 56.0, 63.3,66.4, 71.2, 75.2, 79.9, 84.6, 107–122 (m), 110.9, 111.2, 114.3, 120.0,126.7, 128.3, 128.7, 128.9, 129.3, 131.9, 135.3, 137.8, 148.5, 148.9,158.1; IR (thin film/NaCl) cm⁻¹ 2926, 2857, 1727, 1515, 1464, 1242,1154, 1031; MS (EI) m/z 1208 (M⁺), 1151, 1066, 667; [α]_(D) ²⁰ +3.73° (c0.805, CHCl₃).

[2R]-Butane-1,2,4-triol. To a dry 1 L two-necked flask equipped with apressure-equalizing addition funnel, a magnetic stirring bar and areflux condenser was added THF (200 mL), B(OMe)₃ (100 mL), and(R)-(+)-malic acid (40.0 g, 0.30 mol). To this solution was addeddropwise BH₃—SMe₂ (100 mL, 1.0 mol) over 2 h in a water bath asinstantaneous H₂ evolution occurred throughout the addition. Afterstirring for 20 h at rt, MeOH (200 mL) was added dropwise, and theresulting solution was filtered through a glass frit funnel charged withCelite to remove any solids. The clear, yellow filtrate was concentratedin vacuo to give a yellow oil. The residue was dissolved in MeOH (100mL) and concentrated in vacuo. This was repeated 5 times giving 26.9 gof the triol (85%). The spectral data matched that of the knowncompound.

[2R]-2-(4-Methoxyphenyl)-[1,3]dioxan-4-yl]methanol (88). A solution ofthe triol (5.0 g, 47.1 mmol), p-anisaldehyde (9.62 g, 70.7 mmol), PPTS(0.12 g, 0.047 mmol) in benzene (100 mL) was refluxed for 10 h with theazeotropic removal of H₂O. NaHCO₃ (0.20 g, 2.4 mmol) was added to thesolution and concentrated in vacuo. The crude mixture was purified byflash chromatography (20% to 50% EtOAc in hexanes) to give 88 (65%). ¹HNMR (300 MHz, CDCl₃)−7.41 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H),5.49 (s, 1H), 4.28 (ddd, J=11.1, 5.1, 1.3 Hz, 1H), 4.00–3.95 (m, 2H),3.79 (s, 3H), 3.67–3.64 (m, 2H), 2.04 (br s, 1H), 1.91 (dq, J=12.4, 5.1Hz, 1H), 1.46–1.41 (m, 1H); ¹³C NMR (75 MHz, CDCl₃)−160.1, 132.0, 127.4,113.6, 101.2, 76.6, 66.5, 65.6, 55.3, 26.9.

[2R]-tert-Butyl-[2-(4-methoxyphenyl)-[1,3]dioxan-4-ylmethoxy]diphenylsilane.A solution of alcohol 88 (8.13 g, 36.2 mmol), imidazole (3.9 g, 57.3mmol), and TBDPSCl (10.2 mL, 39.7 mmol) in DMF (75 mL) was stirredovernight at room temperature under argon. A mixture of H₂O (250 mL) andEtOAc (150 mL) was added and the layers were separated. The aqueouslayer was extracted with EtOAc (2×100 mL). The organic layers werecombined and washed with H₂O (2×100 mL), brine (100 mL), dried overMgSO₄, filtered and concentrated in vacuo. The crude oil was purified byflash chromatography (20% EtOAc in hexanes) to yield 15.9 g (95%) of thesilyl ether as a clear yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.69–7.66(m, 4H), 7.41–7.34 (m, 8H), 6.86 (d, J=8.8 Hz, 2H), 5.46 (s, 1H), 4.28(dd, J=11.0, 4.2 Hz, 1H), 4.02–3.96 (m, 2H), 3.86–3.83 (m, 1H), 3.79 (s,3H), 3.67 (dd, J=10.2, 5.6 Hz, 1H), 1.84 (dq, J=12.2, 4.9 Hz, 1H),1.65–1.61 (m, 1H), 1.05 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 160.0, 135.7,133.4, 130.0, 129.6, 128.2, 128.0, 113.4, 101.0, 77.5, 66.9, 66.0, 55.3,28.1, 26.8, 19.3.

4-(tert-Butyldiphenylsilanyloxy)-3-(4-methoxybenzyloxy)-butan-1-ol. To astirred solution of the acetal (5.0 g, 10.8 mmol) in toluene (20 mL) at−78° C. was added slowly via cannula DibalH in toluene (33.0 mL, 1M).The reaction mixture was maintained at −78° C. for 12 h and quenched byslow addition to a vigorously stirred saturated solution of Rochellesalt in H₂O (70 mL). The emulsion was stirred until two layers formed (1h). The aqueous layer was extracted with CH₂Cl₂ (4×15 mL) and theorganic layers were combined, dried over MgSO₄, filtered andconcentrated in vacuo. The crude oil was purified by flashchromotaography (20% to 50% EtOAc in hexanes) providing 4.01 g (80%) ofthe corresponding alcohol as a clear, yellow oil. ¹H NMR (300 MHz,CDCl₃) δ 7.69–7.66 (m, 4H), 7.43–7.38 (m, 6H), 7.20 (d, J=8.5 Hz, 2H),6.86 (d, J=8.5 Hz, 2H), 4.60 (d, J=11.2 Hz, 1H), 4.41 (d, J=11.2 Hz,1H), 3.79 (s, 3H), 3.77–3.66 (m, 5H), 1.82–1.79 (m, 2H), 1.05 (s, 9H);¹³C NMR (75 MHz, CDCl₃) δ 159.3, 135.5, 133.2, 129.4, 129.0, 128.0,127.6, 113.8, 78.3, 72.1, 66.4, 60.2, 55.2, 34.2, 26.8, 19.1.

4-(tert-Butyldiphenylsilanyloxy)-3-(4-methoxybenzyloxy)-butyraldehyde(89). DMSO (0.9 mL, 12.8 mmol) was added, dropwise, to a stirredsolution of oxalyl chloride (0.5 mL, 6.0 mmol) in CH₂Cl₂ (8.0 mL) at−78° C. under argon. The reaction mixture was stirred for 5 min then asolution of the alcohol (2.04 g, 4.41 mmol) in CH₂Cl₂ (27.0 mL) wasadded dropwise. After 1 h at −78° C., Et₃N (3.15 mL, 22.4 mmol) wasadded slowly via syringe, the mixture was stirred for 5 min then warmedto room temperature. The reaction mixture was diluted with CH₂Cl₂ (30mL), washed with ice cold 0.5 M HCl (50 mL) then H₂O (40 mL) and thelayers were separated. The aqueous layers were combined and extractedwith CH₂Cl₂ (2×40 mL) and the combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo. The intermediate aldehyde 89was used in the following reaction without purification: ¹H NMR (300MHz, CDCl₃) δ 9.76 (s, 1H), 7.67–7.63 (m, 4H), 7.44–7.34 (m, 6H), 7.16(d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.52 (d, J=11.1 Hz, 1H), 4.41(d, J=11.1 Hz, 1H), 4.03–3.99 (m, 1H), 3.81 (s, 3H), 3.79–3.74 (m, 2H),3.68–3.63 (m, 1H), 2.67 (dd, J=6.1, 1.9 Hz, 1H), 1.04 (s, 9H).

[3R,4R,6R]-7-(tert-Butyldiphenylsilanyloxy)-6-(4-methoxybenzyloxy)-3-methylhept-1-en-4-ol(90). A solution of (R,R)-diisopropyl tartrate (Z)-crotylboronate (15.0mmol) was added to 4 Å powdered molecular sieves (0.170 g) in toluene(8.4 mL) under argon and the mixture was stirred for 20 min at roomtemperature. The mixture was cooled to −78° C. and a solution of thealdehyde 89 (2.0 g, 4.4 mmol) in toluene (5.0 mL) was added dropwise viacannula. The resulting mixture was maintained at −78° C. for 3 h andthen treated with NaBH₄ (0.072 g, 1.75 mmol) in EtOH (2.0 mL) and warmedto 0° C. The reaction mixture was treated with 1N NaOH (30 mL) andstirred vigorously for 30 min, followed by separation of the organiclayer. The aqueous layer was extracted with CH₂Cl₂ (5×55 mL) and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude oil was purified by flashchromatography (5% to 20% Et₂O in hexanes) providing 1.43 g (63% 2 seps)of alcohol, a clear oil: [α]²⁰ _(D)=+0.32 (c 1.8, CHCl₃); ¹H NMR (300MHz, CDCl₃) δ 7.67 (d, J=7.0 Hz, 2H), 7.45–7.35 (m, 6H), 7.20 (d, J=8.4Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 5.73 (ddd, J=18.2, 11.0, 7.4 Hz, 1H0,5.03 (dd, J=11.0, 1.7 Hz, 1H), 5.02 (dd, J=18.2, 1.7 Hz, 1H), 4.59 (d,J=11.3 Hz, 1H), 4.40 (d, J=11.3 Hz, 1H), 3.79 (s, 3H), 3.89–3.75 (m,2H), 3.68–3.65 (m, 2H), 2.18 (sext, J=6.8 Hz, 1H), 1.84–1.55 (m, 2H),1.05 (s, 9H), 1.01 (d, J=6.8 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ159.0,140.6, 135.6, 133.5 (2C), 130.3, 131.0, 127.6, 129.6, 114.4, 113.6,72.2, 83.1, 64.1, 71.3, 55.2, 40.8, 37.2, 26.8, 19.2, 14.4; IR (thinfilm) 3056, 2989, 2859, 1513, 1426, 1248, 1112, 1077 cm⁻¹; LRMS (EI) 517(M−H), 435, 333, 303, 255, 241, 223, 199, 135, 121 m/z.

[2R,4R,5R]-[2,4-bis-(4-Methoxybenzyloxy)-5-methylhept-6-enyloxy]tert-butyldiphenylsilane. A mixture of NaH (1.8 g, 7.23 mmol) in THF (5 mL) was cooled to0° C. then DMF (5 mL), the alcohol (1.25 g, 2.41 mmol) in THF (5 mL),and PMBBr (1.14 g, 6.03 mmol) were added. The reaction mixture waswarmed to room temperature and stirred for 48 h. The resulting mixturewas poured into a pH 7 phosphate buffer and diluted with ether (85 mL).The organic layer was separated and washed with pH 7 buffer (3×55 mL),dried over K₂CO₃, filtered and concentrated in vacuo. The resultingcrude yellow oil was purified by flash chromatography (5% to 10% EtOAcin hexanes) providing 0.985 g (64%) of the PMB ether a clear, yellowtinted oil: [α]²⁰ _(D)=+0.31 (c 1.8, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ7.69–7.65 (m, 4H), 7.39–7.37 (m, 6H), 7.22–7.19 (m, 4H), 6.86–6.84 (m,4H), 5.73 (ddd, J=17.8, 9.8, 7.0 Hz, 1H), 5.04–4.99 (m, 2H), 4.64 (d,J=11.2 Hz, 1H), 4.49 (d, J=11.1 Hz, 1H), 4.30 (d, J=11.2 Hz, 1H), 4.18(d, J=11.1 Hz, 1H), 3.78 (s, 6H), 3.81–3.52 (m, 4H), 2.60–2.56 (m, 1H),1.57–1.51 (m, 2H), 1.05 (s, 9H), 1.0 (d, J=6.9 Hz, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 159.0, 140.6, 135.6, 133.5 (2C), 130.3, 131.0, 127.6, 129.6,114.4, 113.6, 72.2, 83.1, 64.1, 75.4, 55.2, 40.8, 37.2, 26.8, 19.2,14.4, −5.3; IR (thin film) 3055, 2985, 1422, 1280, 247 cm⁻¹; LRMS (EI)581.34 (M−C₄H₇), 579.34, 522.34, 444, 326, 383, 323, 339, 301, 255, 137,122 m/z.

[2R,3R,5R]-6-(tert-Butyldiphenylsilanyloxy)-3,5-bis-(4-methoxybenzyloxy)-2-methylhexanal.To a solution of MeOH (30 mL), CH₂Cl₂ (10 mL) and a few drops ofpyridine was added the PMB ether (800 mg, 1.25 mmol) and the mixture wascooled to −78° C. Ozone was bubbled through the reaction mixture until aslight purple color was seen. Excess DMS (6.0 mL) was added to thesolution and allowed to warm to RT. After 3 h, the mixture wasconcentrated in vacuo. The yellow residue was dissolved in hexanes (60mL) and washed with H₂O (2×40 mL) and brine (20 mL). The organic layerwas dried over MgSO₄, filtered and concentrated in vacuo to give theintermediate aldehyde (800 mg, 1.25 mmol) that was used in the followingstep without further purification: ¹H NMR (300 MHz, CDCl₃) δ 9.70 (d,J=2.0, 1H), 7.69–7.65 (m, 4H), 7.39–7.37 (m, 6H), 7.22–7.19 (m, 4H),6.86–6.84 (m, 4H), 4.64 (d, J=11.2 Hz, 1H), 4.49 (d, J=11.1 Hz, 1H),4.30 (d, J=11.2 Hz, 1H), 4.18 (d, J=11.1 Hz, 1H), 3.78 (s, 6H),3.81–3.52 (m, 4H), 2.60–2.56 (m, 1H), 1.57–1.51 (m, 2H), 1.05 (s, 9H),1.0 (d, J=6.9 Hz, 3H).

[4R,5R,7R]-8-(tert-Butyldiphenylsilanyloxy)-5,7-bis-(4-methoxybenzyloxy)-4-methyloct-2-enoicacid ethyl ester (91). To a stirred suspension of NaH (36 g, 1.56 mmol)in toluene (10 mL) at 0° C. and under argon was added a solution of2-(diethoxyphosphoryl)propionic acid ethyl ester (0.47 mL, 1.77 mmol) intoluene (0.40 mL) dropwise. The reaction mixture was warmed to rt for 30min then recooled to 0° C. The intermediate aldehyde (0.5 g, 1.3 mmol)in THF (10 mL) was added dropwise and the reaction mixture was stirredat 0° C. for 2 h. The solution was quenched by addition of pH 7 buffer(5 mL) and diluted with Et₂O (12 mL). The emulsion was warmed to rt andthe layers were separated. The organic layer was washed with a saturatedsolution of NH₄Cl (10 mL) and the aqueous layers were combined andextracted with Et₂O (3×20 ml). The organic layers were combined, driedover MgSO₄, filtered and concentrated in vacuo. The crude mixture waspurified by flash chromatography (0% to 20% EtOAc in hexanes) to give623 mg (70% 2 steps) of 91 a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.69–7.65 (m, 4H), 7.39–7.37 (m, 4H), 7.21–7.18 (m, 4H), 6.85–6.83 (m,4H), 6.98 (dd, J=15.7, 7.6 Hz, 1H), 5.82 (dd, J=15.7, 1.0 Hz, 1H), 4.64(d, J=11.2 Hz, 1H), 4.50 (d, J=11.1 Hz, 1H), 4.36 (d, J=11.2 Hz, 1H),4.20 (d, J=11.1 Hz, 1H), 3.78 (s, 6H), 3.81–3.52 (m, 4H), 2.60–2.56 (m,1H), 1.57–1.51 (m, 2H), 1.05 (s, 9H), 1.0 (d, J=6.8 Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 166.3, 158.9, 150.5, 131.0, 130.0, 129.2, 129.1, 121.1,113.5, 78.4, 75.9, 71.7, 71.2, 64.1, 59.9, 55.0, 38.9, 34.1, 25.7, 18.1,14.4, 14.1, −5.5; IR (thin film) 3055, 2956, 2933, 2908, 2857, 1705,1243, 1097 cm⁻¹; HRMS (EI) cald for C₄₃H₅₄O₇Si 710.3628, found 371.3627.

[4R,5R,7R]-8-(tert-Butyldiphenylsilanyloxy)-5,7-bis-(4-methoxybenzyloxy)-4-methyloct-2-en-1-ol.To a stirred solution of ester 91 (600 mg, 0.84 mmol) in CH₂Cl₂ (6 mL)at −40° C. under argon was added slowly over 10 min via syringe DibalHin toluene (9 mL, 1M). After 30 min at 40° C., the reaction mixture wasquenched by slow addition of MeOH (0.6 mL) and warmed to rt. Thereaction mixture was poured into a vigorously stirred solution ofsaturated Rochelle salt in H₂O (8 mL) and EtOAc (12 mL) and stirredovernight. The aqueous layer was separated and extracted with EtOAc (3×5mL), dried over MgSO₄, filtered and concentrated in vacuo. The crudemixture was purified by flash chromatography (20% EtOAc in hexanes) toproduce 450 mg (80%) of the alcohol, a clear liquid: ¹H NMR (300 MHz,CDCl₃) δ 7.70–7.66 (m, 4H), 7.39–7.35 (m, 6H), 7.21–7.18 (m, 4H),6.85–6.82 (m, 4H), 5.68–5.65 (m, 2H), 4.64 (d, J=11.1 Hz, 1H), 4.51 (d,J=11.0 Hz, 1H), 4.46 (d, J=11.1 Hz, 1H), 4.24 (d, J=11.0 Hz, 1H),4.10–4.06 (m, 2H), 3.78 (s, 6H), 3.81–3.52 (m, 4H), 2.60–2.56 (m, 1H),1.57–1.51 (m, 2H), 1.05 (s, 9H), 1.03 (d, J=6.8 Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 159.0, 135.6, 135.1, 133.5 (2C), 131.1, 130.3, 130.0,127.6, 129.4, 129.6, 83.1, 75.2, 72.4, 72.2, 64.4, 63.7, 55.2, 34.7,26.8, 19.2, 15.4; IR (thin film) 3295, 3045, 2958, 2941, 2910, 2857,1241, 1097 cm⁻¹; HRMS (EI) cald for C₄₁H₅₂O₆Si 668.3599, found 668.3596.

[2R,3R,5R]-8-(tert-Butyldiphenylsilanyloxy)-5,7-bis-(4-methoxybenzyloxy)-4-methyloct-2-enal. To a solution of the alcohol (400 mg, 0.59 mmol) in CH₂Cl₂(2 mL) was added Dess-Martin periodane (330 mg, 0.78 mmol) and thereaction mixture was stirred for 30 min. The reaction mixture wasdiluted with Et₂O (10 mL) and poured into a stirring solution ofsaturated Na₂S₂O₃ (5 mL) and saturated NaHCO₃ (5 mL). The layers wereseparated and the organic layer was washed with saturated NaHCO₃ (3×5mL), dried over MgSO₄, filtered and concentrated in vacuo to give theintermediate aldehyde which was used in the next reaction withoutfurther purification: ¹H NMR (300 MHz, CDCl₃) δ 9.50 (d, 7.8 Hz, 1H),7.69–7.64 (m, 4H), 7.39–7.37 (m, 7H), 7.20–7.14 (m, 4H), 6.84–6.79 (m,4H), 6.10 (dd, J=7.8, 17.0 Hz, 1H), 4.64 (d, J=11.2 Hz, 1H), 4.49 (d,J=11.1 Hz, 1H), 4.30 (d, J=11.2 Hz, 1H), 4.18 (d, J=11.1 Hz, 1H), 3.78(s, 6H), 3.81–3.52 (m, 4H), 2.60–2.56 (m, 1H), 1.57–1.51 (m, 2H), 1.05(s, 9H), 1.00 (d, J=6.9 Hz, 3H).

[4R,5R,7R]-10-(tert-butyldiphenysilanyloxy)-7,9-bis(4-methoxybenzyloxy)-6-methyldeca-2,4-dienoicacidmethyl ester. To a stirred solution of[bis-(2,2,2-trifluoroethoxy)phosphoryl]acetic acid methyl ester (210 mg,0.65 mmol) in THF (12 mL) at −78° C. under argon was added dropwiseKHMDS in toluene (1.4 mL, 0.5 M). The reaction mixture was warmed to−40° C. for 1 h then cooled to −78° C. and the intermediate aldehyde(400 mg, 0.59 mmol) in THF (0.5 mL) was added dropwise. After 3 h at−78° C., the solution was warmed to 0° C. and quenched by addition of asaturated solution of NH₄Cl (5 mL) and diluted with Et₂O (5 mL). Theaqueous layer was separated and extracted with diethyl ether (5×3 mL).The combined organic phases were washed with brine (5 mL), dried overMgSO₄, filtered and concentrated in vacuo. The crude mixture waspurified by flash chromatography (10% to 30% EtOAc in hexanes), yielding220 mg (65% 2 steps) of conjugated ester, a clear oil: ¹H NMR (300 MHz,CDCl₃) δ 7.69–7.65 (m, 4H), 7.39–7.37 (m, 7H), 7.20–7.16 (m, 4H),6.85–6.79 (m, 4H), 6.64 (t, J=11.2 Hz, 1H), 6.22 (ddd, J=15.4, 6.8 Hz,1H), 5.87 (d, J=11.2 Hz, 1H), 5.04–4.99 (m, 2H), 4.64 (d, J=11.2 Hz,1H), 4.49 (d, J=11.1 Hz, 1H), 4.30 (d, J=11.2 Hz, 1H), 4.18 (d, J=11.1Hz, 1H), 3.78 (s, 6H), 3.81–3.52 (m, 4H), 2.60–2.56 (m, 1H), 1.57–1.51(m, 2H), 1.05 (s, 9H), 1.00 (d, J=6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ166.9, 147.3, 145.4, 135.6, 133.5 (2C), 130.3, 129.6, 126.7, 115.5,113.5, 78.4, 75.9, 71.7, 71.8, 64.1, 55.0, 51.1, 39.7, 34.1, 26.8, 19.2,14.1; IR (CH₂Cl₂) 3048, 2987, 2931, 2875, 2822, 1715, 15251, 1423, 1250,1110 cm⁻¹; HRMS (EI) cald for 722.3642, found 722.3640 m/z.

[6R,7S,9R]-10-Hydroxy-7,9-bis-(4-methoxybenzyloxy)-6-methyldeca-2,4-dienoicacid Methyl Ester (92). To a solution of the TBDPS ether (100 mg, 0.14mmol) in THF 1 ml) was slowly added HF-pyridine in pyridine (1.5 ml,prepared by slow addition of 0.45 ml pyridine to 0.1 ml HF-pyridinecomplex followed by dilution with 0.94 ml THF) at 0° C. The mixture waswarmed to room temperature and stirred overnight at room temperature.The reaction mixture was slowly quenched with saturated NaHCO₃ (5 mL)and the aqueous layer was separated and extracted with CH₂Cl₂ (5×2 mL).The combined organic layers were washed with saturated CuSO₄ (2 mL),dried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified by flash chromatography (25% EtOAc in hexanes) affording 50mg (75%) of alcohol 92: [α]²⁰ _(D)=+8.56 (c 0.1, CHCl₃); ¹H NMR (300MHz, CDCl₃) δ 7.53 (dd, J=15.0, 11.4 Hz, 1H), 7.35–7.30 (m, 4H),6.97–6.93 (m, 6H), 6.65 (dd, J=11.3, 1.3 Hz, 1H), 6.23 (dd, J=15.0, 6.9Hz, 1H), 5.69 (d, J=11.3 Hz, 1H), 4.64 (d, J=10.9 Hz, 1H), 4.59 (d,J=11.2 Hz, 1H), 4.44 (d, J=11.2 Hz, 1H), 4.34 (d, J=10.9 Hz, 1H), 3.88(s, 3H), 3.82 (s, 3H), 2.77–2.73 (m, 2H), 3.67–3.64 (m, 1H), 3.54 (dd,J=3.6, 11.5 Hz, 1H), 2.95–2.89 (m, 1H), 1.90–1.81 (m, 2H), 1.19 (d,J=6.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 159.0, 147.3, 145.4,130.1, 130.3, 129.7, 126.7, 115.5, 113.6, 75.9, 78.5, 71.1, 63.9, 55.0,51.0, 38.4, 33.7, 14.1; IR (thin film) 3315, 3055, 2986, 2858, 1710,1513, 1423, 1247, 1105 cm⁻¹; LRMS (EI) 484, 469, 349, 425, 223, 121 m/z;HRMS (EI) calcd for C₂₈H₃₆O₇ 484.2582, found 484.2579.

(R,R)-diisopropyl tartrate (Z)-crotylboronate. An oven-dried 1 Lthree-neck round bottom flask equipped with a magnetic stir bar and a−100° C. thermometer was charged with 206 mL of anhydrous THF and KOtBu(28.2 g, 250 mmol). This mixture was flushed with Ar and cooled to −78°C., then cis-2-butene (23 mL, 250 mmol), condensed from a gas lecturebottle into a rubber-stoppered round bottom flask immersed in a −78° C.dry ice-acetone bath, was poured into the reaction mixture. n-BuLi (100mL, 2.5 M in hexane) was then added dropwise via cannula over 1.5 h.After completion of the addition, the cooling bath was removed and thereaction mixture was allowed to warm to −20 to −25° C. for 30 min beforebeing recooled to −78° C. Triisopropylborate (57.8 mL, 250 mmol) wasadded drop-wise via cannula to the (Z)-crotylpotassium solution over 2h. After addition, the reaction mixture was maintained at −78° C. for 30min and then rapidly poured into a 2 L separatory funnel containing 470mL of 1 N HCl saturated with NaCl. The aqueous layer was adjusted to pH1 by using 1 N HCl (100–150 mL), and then a solution of(R,R)-diisopropyl tartrate (52.8 g, 250 mmol) in 88 mL of Et₂O wasadded. The phases were separated, and the aqueous layer was extractedwith additional Et₂O (4×120 mL). The combined extracts were dried overMgSO₄ for 1 h then vacuum filtered through a fritted glass funnel underAr blanket into an oven-dried round-bottom flask. The filtrate wasconcentrated in vacuo, and pumped to constant weight at under vacuum.Anhydrous toluene (170 mL) was added to the flask make a 1M solution.

[4S,3S,2R]-4-Benzyl-3-(3-hydroxy-2,4-dimethylpent-4-enoyl)oxazolidin-2-one(93). Oxazolidinone 4 (10.0 g, 43.1 mmol) was treated with MgCl₂ (0.20g, 2.2 mmol), NaSbF₆ (1.7 g, 6.5 mmol), Et₃N (6.03 mL, 86.2 mmol),methacrolein (2.67 mL, 25.9 mmol) and TMSCl (3.92 mL, 32.3 mmol) inEtOAc (50 mL) and allowed to stir under Ar at rt for 24 h. Theyellow-green slurry was filtered through a plug of silica gel with Et₂O(1 L). GC analysis of the solution gave the isomeric composition of theTMS ether in a 16:1 ratio with its diastereomers. The ether wasconcentrated in vacuo, and MeOH (86 mL) and TFA (1 mL) was added. Thereaction mixture was stirred for 30 min and concentrated to give ayellow which was purified by flash chromatography (10% acetone inhexanes) to yield 5.02 g of alcohol 93 (78% 2 steps). Data matches knownliterature.³² [α]²⁰ _(D)=+0.06 (c 0.1, CHCl ₃); ¹H NMR (300 MHz, CDCl₃)δ 7.39–7.31 (m, 5H), 5.08 (s, 1H), 5.02 (s, 1H), 4.77–4.75 (m, 1H),4.27–4.22 (m, 4H), 3.35 (dd, J=13.5, 3.2 Hz, 1H), 2.83 (dd, J=13.5, 9.5Hz, 1H), 2.75 (br s, 1H), 1.86 s (3H), 1.19 (d, J=6.7 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 175.6, 152.9, 145.0, 135.7, 129.3, 128.9, 127.1,114.5, 80.1, 65.6, 55.5, 41.9, 38.4, 16.1, 14.7; IR (thin film) 3300,3057, 2931, 2857, 1781, 1702, 1422, 1384, 1271, 1209, 1079 cm⁻¹; HRMS(EI) cald for C₁₇H₂₁NO₄ 303.1582, found 303.1581.

[4R,2S,3R]-4-Benzyl-3-[3-(tert-butyldimethylsilanyloxy)-2,4-dimethylpent-4-enoyl]oxazolidin-2-one.To a stirred solution of alcohol 93 (20.24 g, 66.72 mmol) in CH₂Cl₂ (170mL) at 0° C. under argon was added 2,6-lutidine (9.3 mL, 79.85 mmol) andTBSOTf (16.1 mL, 73.4 mmol). After 3 h at 0° C. the reaction mixture wasquenched with MeOH (34 mL) then concentrated to dryness. The residue wastaken up in Et₂O (225 mL) and washed with a saturated solution of NH₄Cl(2×50 mL). The aqueous layers were combined and extracted with Et₂O(2×20 mL) and the combined organic layers were dried over MgSO₄ andconcentrated in vacuo. Flash chromatography of the crude mixture (10% to20% EtOAc in hexanes) gave 26.5 g (95%) of the silyl ether as a clearoil: [α]²⁰ _(D)=+0.07 (c 0.15, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ7.40–7.29 (m, 5H), 5.00 (s, 1H), 4.98 (s, 1H), 4.72 (dq, J=7.0, 3.2 Hz,1H), 4.51 (d, J=9.6 Hz, 1H), 4.21–4.18 (m 3H), 3.49 (dd, J=13.3, 3.2 Hz,1H), 2.64 (dd, J=13.3, 10.2 Hz, 1H), 1.80 (s, 3H), 1.03 (d, J=7.0 Hz,3H), 0.9 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ175.9, 153.1, 145.0, 135.7, 129.3, 128.9, 127.2, 114.6, 79.4, 65.8,55.5, 41.9, 38.4, 25.8, 18.1, 16.1, 14.7, −4.7, −5.1; IR (thin film)3047, 2938, 2854, 1779, 1702, 1429, 1380, 1271, 1210, 1082 cm⁻¹; LRMS(EI) 417, 402, 360, 290, 234, 185, 117; HRMS (EI) calcd for C₂₃H₃₅NO₄Si417.2335, found 417.2345.

[4S,2S,3R]-4-Benzyl-3-[3-(tert-butyldimethylsilanyloxy)-5-hydroxy-2,4-dimethylpentanoyl]oxazolidin-2-one(94). A stirred solution of 9-BBN in THF (29 mL, 0.5 M) was treated withthe alkene (5.0 g, 11.97 mmol) in THF (29 mL). The reaction mixture wasstirred at rt for 24 h, then treated sequentially with 1:1 EtOH-THF (29mL), pH 7 buffer (29 mL) and 30% aq. H₂O₂ (14.5 mL) and stirred for 12 hat rt. The mixture was extracted with diethyl ether (3×20 mL). Thecombined organic layers were washed with H₂O (15 mL) and saturatedaqueous NaCl (15 mL) then dried over MgSO₄, filtered and concentrated invacuo. Purification of the mixture by flash chromatography (20% EtOAc inhexanes) gave 94 as a clear oil (3.91 g, 75%): [α]²⁰ _(D)=+0.24 (c 0.05,CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.33–7.23 (m, 5H), 4.69–4.60 (m, 1H),4.21 (dd, J=6.8, 3.8 Hz, 1H), 4.17–4.04 (m, 3H), 3.77–3.60 (m 2H), 3.44(dd, J=13.1, 3.2 Hz, 1H), 2.60 (dd, J=13.1, 10.7 Hz, 1H), 2.50 (br s,1H), 2.02–1.85 (m, 1H), 1.23 (d, J=6.9 Hz, 3H), 1.00 (d, J=7.0 Hz, 3H),0.9 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ174.7, 153.1, 135.4, 129.3, 129.0, 127.3, 66.1, 65.4, 55.8, 43.9, 38.3,37.0, 26.7, 26.0, 18.2, 16.4, 12.4, −4.2, −4.8; IR (thin film) 3538,2927, 1780, 1700, 1273, 1201 cm⁻¹; HRMS (EI) cald for C₂₃H₃₇NO₅Si435.2461, found 435.2460.

(4S)-[2R,3R,4R]-Benzyl-3-[3,5-bis(tert-butyldimethylsilanyloxy)-2,4-dimethylpentanoyl]oxazolidin-2-one.To a stirred solution of alcohol 94 (2.6 g, 5.97 mmol) in CH₂Cl₂ (15 mL)at 0° C. under argon was added 2,6-lutidine (0.83 mL, 7.14 mmol) andTBSOTf (1.44 mL, 6.57 mmol). After 3 h at 0° C. the reaction mixture wasquenched with MeOH (3 mL) then concentrated to dryness. The residue wastaken up in Et₂O (20 mL) and washed with a saturated solution of NH₄Cl(2×5 mL). The aqueous layers were combined and extracted with Et₂O (2×5mL) and the combined organic layers were dried over MgSO₄ andconcentrated in vacuo. Flash chromatography of the crude mixture (10% to20% EtOAc in hexanes) gave 3.01 g (95%) of the silyl ether as a clearoil: [α]²⁰ _(D)=+0.24 (c 0.05, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ7.33–7.22 (m, 5H), 4.69–4.61 (m, 1H), 4.24 (dd, J=3.7, 7.0 Hz, 1H),4.13–4.11 (m, 3H), 3.76 (dd, J=6.0, 10.3 Hz, 1H), 3.48–3.42 (m, 2H),2.60 (dd, J=10.3, 13.1 Hz, 1H), 2.01–1.87 (m, 1H), 1.17 (d, J=7.0 Hz,3H), 0.976 (d, J=7.0 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H),0.08 (s, 3H), 0.05 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 175.5, 153.1,135.7, 129.3, 129.0, 127.3, 74.4, 66.0, 64.9, 55.7, 43.2, 39.9, 38.5,26.1, 26.0, 18.3, 14.4, 13.5, −4.0, −4.6, −5.4 (2C); IR (thin film)3057, 2952, 2860, 1781, 1699, 1382, 1259, 1100 cm⁻¹; LRMS (EI) 492(M−C₄H₉), 377, 374, 199, 177, 115; HRMS (EI) calcd for C₂₅H₄₂NO₅Si₂492.3306, found 492.3301.

[2R,3R,4R]-3,5-bis(tert-Butyldimethylsilanyloxy)-2,4-dimethylpentan-1-ol(95). To a stirred solution of silyl ether (5 g, 9.09 mmol) in THF (50mL) at 0° C. were added MeOH (1.14 mL, 27.3 mmol) and LiBH₄ in THF (14mL, 2M) under argon. The solution was stirred at 0° C. for 30 min andthen quenched by the addition of a saturated solution of Rochelle saltin H₂O (60 mL) and stirred for 10 min at 0° C. The mixture was pouredinto CH₂Cl₂ (100 mL) and stirred vigorously until 2 layers appeared (2h). The aqueous layer was separated extracted with of CH₂Cl₂ (40 mL).The combined organic layers were washed with brine (40 mL), dried(MgSO₄), filtered and concentrated in vacuo. Flash chromatography (30%EtOAc in hexanes) gave 2.32 g (65%) of alcohol 95 as a colorless oil:[α]²⁰ _(D)=+10.0 (c 1.2, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 3.67 (t,J=5.2 Hz, 1H), 3.55–3.50 (m, 3H), 3.39 (dd, J=10.0, 6.5 Hz, 1H), 2.98(br s, 1H), 1.87–1.77 (m, 2H), 0.92 (d, J=7.0 Hz, 3H), 0.86 (d, J=7.0Hz, 3H), 0.83 (s, 9H), 0.81 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H), −0.03(s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 800.2, 66.0, 65.2, 39.7, 38.8, 25.9,25.6, 18.3, 18.0, 14.9, 14.7, −5.4, −5.3, −4.1; IR (thin film) 3330,2930, 2858, 1471, 1250, 1023 cm⁻¹; HRMS (EI) calcd for C₁₉H₄₄O₃Si₂376.2859, found 376.2858.

[2R,3R,4R]-3,5-bis-(tert-Butyldimethylsilanyloxy)-2,4-dimethylpentanal(96). Following the procedure for4-(tert-butyldiphenylsilanyloxy)-3-(4-methoxybenzyloxy)-butyraldehyde89, 96 can be prepared in a similar manner.

(2R)-3-(tert-Butyldimethylsilanyloxy)-2-methylpropionic acid methylester. A solution of alcohol (10.0 g, 84.6 mmol), imidazole (9.2 g,133.9 mmol), and TBSCl (19.1 g, 126.9 mmol) in DMF (150 mL) was stirredovernight at room temperature under argon. A mixture of H₂O (500 mL) andEtOAc (300 mL) was added and the layers were separated. The aqueouslayer was extracted with EtOAc (2×200 mL). The organic layers werecombined and washed with H₂O (2×200 mL), brine (200 mL), dried overMgSO₄, filtered and concentrated in vacuo. The crude oil was purified byflash chromatography (20% EtOAc in hexanes) to yield 17.7 g (90%) of thesilyl ether as a clear yellow oil: The spectral data matched that of theknown compound. ¹H NMR (300 MHz, CDCl₃) δ 3.62 (dd, J=6.7, 7.0 Hz, 1H),3.50 (dd, J=6.7, 7.0 Hz, 1H), 3.50 (m, 3), 2.48 (sext, J=7.0 Hz, 1H),0.97 (d, J=7.0 Hz, 3H), 0.71 (s, 9H), −0.1 (s, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 175.4, 65.2, 51.5, 42.5, 25.7, 18.2, 13.4, −5.5.

[2R]-3-(tert-Butyldimethylsilanyloxy)-2-methylpropan-1-ol. To a stirredsolution of silyl ether (5.0 g, 21.5 mmol) in CH₂Cl₂ (125 mL) at −40° C.under argon was added slowly over 1.5 h via cannula DibalH in toluene(100 mL, 1M). After 30 min at −40° C., the reaction mixture was quenchedby slow addition of MeOH (15 mL) and warmed to RT. The reaction mixturewas poured into a vigorously stirred solution of saturated Rochelle salt(200 mL) and EtOAc (300 mL) and stirred overnight. The aqueous layer wasseparated and extracted with EtOAc (3×50 mL), dried (MgSO₄) andconcentrated in vacuo. The crude mixture was purified by flashchromatography (20% EtOAc in hexanes) to produce 3.46 g (79%) of thealcohol, a clear liquid. The spectral data matched that of the knowncompound: ¹H NMR (300 MHz, CDCl₃) δ 3.73 (dd, J=4.5, 9.8, Hz, 1H), 3.57(m, 3H), 2.80 (br s, 1H), 1.99–1.86 (m, 1H), 0.89 (s, 9H), 0.82 (d,J=7.0 Hz, 3H), 0.06 (d, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 68.8, 68.4, 37.0,25.8, 18.1, 13.0, −5.6.

[2R]-3-(tert-Butyldimethylsilanyloxy)-2-methyl propionaldehyde (ent-17).DMSO (3.0 mL, 42.6 mmol) was added, dropwise, to a stirred solution ofoxalyl chloride (1.5 mL, 19.9 mmol) in CH₂Cl₂ (80 mL) at −78° C. underargon. The reaction mixture was stirred for 5 min then a solution ofalcohol (3.0 g, 14.7 mmol) in CH₂Cl₂ (25 mL) was added dropwise. After 1h at −78° C., Et₃N (10.5 mL, 74.7 mmol) was added slowly via syringe,the mixture was stirred for 5 min then warmed to room temperature. Thereaction mixture was diluted with CH₂Cl₂ (25 mL), washed with ice cold0.5 M HCl (50 mL) then H₂O (30 mL) and the layers were separated. Theaqueous layers were combined and extracted with CH₂Cl₂ (2×30 mL) and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The intermediate aldehyde ent-17 was used in thefollowing reaction without purification: ¹H NMR (300 MHz, CDCl₃) δ 9.75(δ, 1.5 Hζ, 1H), 3.86–3.82 (m, 2H), 2.53–2.50 (m, 1H), 1.10 (d, J=7.0Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H).

[3S,4S,5S]-2,4-dimethyl-1-[(tert-butyldimethylsilyl)oxy]-hexene-5-en-3-ol(97). A solution of (R,R)-diisopropyl tartrate (E)-crotylboronate (22.1mmol) was added to 4 Å powdered molecular sieves (0.025 g) in toluene (1mL) under argon and the mixture was stirred for 20 min at roomtemperature. The mixture was cooled to −78° C. and a solution of thealdehyde ent-17 (3.0 g, 14.7 mmol) in toluene (8 mL) was added dropwisevia syringe. The resulting mixture was maintained at −78° C. for 3 h andthen treated with NaBH₄ (0.106 g, 2.6 mmol) in EtOH (4 mL) and warmed to0° C. The reaction mixture was treated with 1N NaOH (40 mL) and stirredvigorously for 30 min, followed by separation of the organic layer. Theaqueous layer was extracted with CH₂Cl₂ (5×80 mL) and the combinedorganic layers were dried over MgSO₄, filtered, and concentrated invacuo. The crude oil was purified by flash chromatography (5% to 25%Et₂O in hexanes) providing 2.87 g (65%) of 97, a clear, yellow tintedoil: ¹H NMR (300 MHz, CDCl₃) δ 5.91 (ddd, J=8.8, 12.0, 15.8 Hz, 1H),5.05 (dd, J=1.8, 12.0 Hz, 1H), 5.04 (dd, J=1.8, 15.8 Hz, 1H), 3.81 (s,1H), 3.73 (dd, J=4.2, 9.8 Hz, 1H), 3.60 (dd, J=8.2, 9.8 Hz 1H), 3.37(dd, J=3.0, 4.8 Hz, 1H), 2.39–2.29 (m, 1H), 1.83–1.70 (m, 1H), 1.09 (d,J=6.9 Hz, 3H), 0.89 (s, 9H), 0.81 (d, J=6.9 Hz, 3H), 0.06 (s, 6H); ¹³CNMR (75 MHz, CDCl₃) δ 139.9, 114.9, 80.2, 68.7, 41.2, 37.5, 25.8 [2C],18.1, 17.7, 13.4, −5.6, −5.7.

[2S,3S,4S]-tert-Butyl-[3-(4-methoxybenzyloxy)-2,4-dimethylhex-5-enyloxy]dimethylsilane.A mixture of NaH (2.9 g, 11.6 mmol) in THF (5 mL) was cooled to 0° C.then DMF (5 mL), alcohol 97 (1.0 g, 3.87 mmol) in THF (5 mL), and PMBBr(1.8 g, 9.7 mmol) were added. The reaction mixture was warmed to roomtemperature and stirred for 48 h. The resulting mixture was poured intoa pH 7 phosphate buffer and diluted with ether (90 mL). The organiclayer was separated and washed with pH 7 buffer (3×60 mL), dried overK₂CO₃, filtered and concentrated in vacuo. The resulting crude yellowoil was purified by flash chromatography (5% to 10% EtOAc in hexanes)providing 1.39 g (75%) of the PMB ether as a clear, yellow tinted oil:[α]²⁰ _(D)=+0.06 (c 1.3, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.31 (d,J=8.6 Hz, 2H), 6.90 (d, J=8.6 Hz, 2H), 5.93 (ddd, J=15.6, 12.0, 8.3 Hz,1H), 5.05 (d, J=12 Hz, 1H), 5.04 (d, J=15.6 1H), 3.89 (s, 3H), 3.29 (dd,J=4.6, 2.9 Hz, 1H), 2.51–2.49 (m, 1H), 1.91–1.86 (m, 1H), 1.01 (d, J=6.9Hz, 3H), 0.08 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 158.9, 142.1, 131.2,129.2, 114.0, 113.6, 82.8, 74.1, 65.7, 55.7, 38.4, 37.3, 25.9, 18.2,15.6, 11.2, −5.2; IR (thin film) 3057, 2957, 2857, 1612, 1513, 1246,1085 cm⁻¹; LRMS (EI) 323 (M−C₄H₇), 321, 271, 255, 186, 122 m/z.

[2S,3S,4S]-5-(tert-Butyldimethylsilanyloxy)-3-(4-methoxybenzyloxy)-2,4-dimethylpentanal (98). Following the procedure for[2R,3R,5R]-6-(tert-Butyldiphenylsilanyloxy)-3,5-bis-(4-methoxybenzyloxy)-2-methylhexanal,98 can be prepared in a similar manner.

(R,R)-Diisopropyl tartrate (E)-crotylboronate. An oven-dried 1 Lthree-neck round bottom flask equipped with a magnetic stir bar and a−100° C. thermometer was charged with 206 mL of anhydrous THF and KOtBu(28.2 g, 250 mmol). This mixture was flushed with Ar and cooled to −78°C., then trans-2-butene (23 mL, 250 mmol), condensed from a gas lecturebottle into a rubber-stoppered round bottom flask immersed in a −78° C.dry ice-acetone bath, was poured into the reaction mixture. n-BuLi (100mL, 2.5 M in hexane) was then added dropwise via cannula over 1.5 h.After completion of the addition, the cooling bath was removed and thereaction mixture was allowed to warm to an internal temperature of −50°C. for 15 min then immediately recooled to −78° C. Triisopropylborate(57.8 mL, 250 mmol) was added drop-wise via cannula to the(E)-crotylpotassium solution over 2 h. After addition, the reactionmixture was maintained at −78° C. for 30 min and then rapidly pouredinto a 2 L separatory funnel containing 470 mL of 1 N HCl saturated withNaCl. The aqueous layer was adjusted to pH 1 by using 1 N HCl (100–150mL), and then a solution of (R,R)-diisopropyl tartrate (52.8 g, 250mmol) in 88 mL of Et₂O was added. The phases were separated, and theaqueous layer was extracted with additional Et₂O (4×120 mL). Thecombined extracts were dried over MgSO₄ for 1 h then vacuum filteredthrough a fritted glass funnel under Ar blanket into an oven-driedround-bottom flask. The filtrate was concentrated in vacuo, and pumpedto constant weight at under vacuum. Anhydrous toluene (170 mL) was addedto the flask make a 1M solution.

Biology

General. Tubulin without microtubule-associated proteins was preparedfrom fresh bovine brains.[32] The normoisotopic and tritiated forms ofpaclitaxel and normoisotopic docetaxel were provided by the DrugSynthesis and Chemistry Branch, National Cancer Institute.(+)-Discodermolide was from Novartis Pharmaceutical Corporation. Ca²⁺-and Mg²⁺-free RPMI-1640 culture medium were from GIBCO/BRL-LifeTechnologies. Fetal bovine serum (FBS) was from Hyclone. Cell lines wereobtained from American Type Culture Collection (Manassas, Va.).

Tubulin Polymerization.[32] Tubulin assembly was followed in aBeckman-Coulter 7400 spectrophotometer, equipped with an electronicPeltier temperature controller, reading absorbance (turbidity) at 350nm. Reaction mixtures (0.25 mL final volume) contained tubulin (finalconcentration 10 μM; 1 mg/mL), monosodium glutamate (0.8 M from a stocksolution adjusted to pH 6.6 with HCl), DMSO (final volume 4% v/v), anddiffering concentrations of test agent where indicated. Reactionmixtures without test agent were cooled to 0° C. and added to cuvettesheld at 0.25–0.5° C. in the spectrophotometer. Test agent in DMSO wasthen rapidly mixed in the reaction mixture. Each run contained onepositive control (paclitaxel, 10 μM final concentration) and onenegative control (DMSO only). Baselines were established at 0.25–2.5° C.and temperature was rapidly raised to 30° C. (in approximately 1 min)and held there for 20 min. The temperature was then rapidly lowered backto 0.25–2.5° C.

Cell Growth Inhibition[34] Cells were plated (500–2000 cells/welldepending on the cell line) in 96-well microplates, allowed to attachand grow for 48 h, then treated with vehicle (4% DMSO, a concentrationthat allowed doubling times of 24 h or less) or test agent (50, 10, 2,0.4 and 0.08 μM for the new agents; 0.001, 0.005, 0.010, 0.020 and 0.100μM for paclitaxel and discodermolide) for the given times. One plateconsisted of cells from each line used for a time zero cell numberdetermination. The other plates in a given determination contained eightwells of control cells, eight wells of medium and each agentconcentration tested in quadruplicate. Cell numbers were obtainedspectrophotometrically (absorbance at 490 nm minus that at 630 nm) in aDynamax plate reader after treatment with3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS) using phenazine methanesulfonate as the electron acceptor. Afterinitial screening with the above 5-fold dilutions, fifty percent growthinhibitory concentration (GI₅₀) values were determined for each agent byrepeating the screen using 2-fold dilutions (five concentrations)centered on the initial estimated GI₅₀ concentration, again inquadruplicate.

Paclitaxel binding site inhibition assay. [34] A stock solution of[³H]paclitaxel (26.8 μM, 16.2 Ci/mmol), obtained from the NCI, wasprepared in 37% (v/v) DMSO. The test agents were prepared in 25% (v/v)DMSO-0.75 M monosodium glutamate (prepared from a 2M stock solutionadjusted to pH 6.6 with HCl). The radiolabeled paclitaxel and testagents, as indicated in terms of final concentrations, were mixed inequal volumes and warmed to 37° C. A reaction mixture (50 μL) containing0.75 M monosodium glutamate, 4.0 μM tubulin, and 40 μM ddGTP (anon-hydrolyzable analog of GTP) was prepared and incubated at 37° C. for30 min to preform microtubules. An equivalent volume of drug mixturewith [³H]paclitaxel was added to preformed polymer and incubated for 30min at 37° C. Bound [³H]paclitaxel was separated from free drug bycentrifugation of the reaction mixtures at 14000 rpm for 20 min at roomtemperature. Non-specific binding was determined by addition of a12-fold excess of docetaxel. Radioactive counts from the supernatant (50μL) were determined by scintillation spectrometry. Bound [³H]paclitaxelwas calculated from the following: total paclitaxel added to eachreaction mixture minus the paclitaxel present in the supernatant (freedrug). The % bound values were normalized to the control values with noinhibitor added.

The foregoing description and accompanying drawings set forth thepreferred embodiments of the invention at the present time. Variousmodifications, additions and alternative designs will, of course, becomeapparent to those skilled in the art in light of the foregoing teachingswithout departing from the scope of the invention. The scope of theinvention is indicated by the following claims rather than by theforegoing description. All changes and variations that fall within themeaning and range of equivalency of the claims are to be embraced withintheir scope.

1. A compound of the following structure

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom; R² is H, an alkyl group, a benzylgroup, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); R^(a),R^(b) and R^(c) are independently an alkyl group or an aryl group; R^(d)is an alkyl group, an aryl group, an alkoxylalkyl group,—R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an alkylenegroup; R^(e) is an alkyl group, an allyl group, a benzyl group, an arylgroup, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) areindependently H, an alkyl group or an aryl group; R³ is (CH₂)_(n) wheren is and integer in the range of 0 to 5, —CH₂CH(CH₃)—, —CH═CH—,—CH═C(CH₃)—, or —C≡C—; R⁴ is (CH₂)_(p) where p is an integer in therange of 4 to 12,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH(R^(s2))C(R^(s3))═C(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))CH(R^(s3))CH(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH(R^(s2))CH(R^(s3))CH(R^(s4))—,wherein y1 and y2 are 1 and y3, y4 and y5 are independently 0 or 1,R^(k1), R^(k2), R^(k3), R^(k4) and R^(k5) are independently H, CH₃, orOR^(2a), and R^(s1), R^(s2), R^(s3), and R^(s4) are independently H orCH₃, wherein R^(2a) is H, an alkyl group, an aryl group, a benzyl group,a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); and R⁵ is Hor OR^(2b), wherein R^(2b) is H, an alkyl group, an aryl group, a benzylgroup, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e);provided that the compound is not dictyostatin
 1. 2. The compound ofclaim 1 with the following stereostructure, or its enantiomer

wherein R¹ is alkenyl; R² is H; R³ is —CH₂CH(CH₃) or —CH═C(CH₃); and R⁴is—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))—wherein y1–y4 are 1, y5 is 0, R^(k1) and R^(k3) are OH, R^(k2) is H,R^(k4) is CH₃, R^(s1), R^(s2), R^(s3) and R^(s4) are H, and R⁵ is OH. 3.The compound of claim 2 wherein R¹ is —CH═CH₂ and R⁴ is


4. The compound of claim 2 wherein R¹ is —CH═CH₂ and R⁴ is:


5. A process for conversion of a first compound with the formula

wherein R¹ is H, an alkyl group, an aryl group, an alkenyl group, analkynyl group, or a halogen atom; R² is H, an alkyl group, a benzylgroup, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); R^(2d)is H R^(a), R^(b) and R^(c) are independently an alkyl group or an arylgroup; R^(d) is an alkyl group, an aryl group, an alkoxylalkyl group,—R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an alkylenegroup; R^(e) is an alkyl group, an allyl group, a benzyl group, an arylgroup, an alkoxy group, or —NR^(g)R^(h), wherein R^(g) and R^(h) areindependently H, an alkyl group or an aryl group; R³ is (CH₂)_(n) wheren is and integer in the range of 0 to 5, —CH₂CH(CH₃)—, —CH═CH—,—CH═C(CH₃)—, or —C≡C—; R⁴ is (CH₂)_(p) where p is an integer in therange of 4 to 12,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))CH(R^(s3))CH(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH(R^(s2))CH(R^(s3))CH(R^(s4))—,wherein y1 and y2 are 1 and y3, y4 and y5 are independently 0 or 1,R^(k1), R^(k2), R^(k3), R^(k4) and R^(k5) are independently H, CH₃, orOR^(2a), and R^(s1), R^(s2), R^(s3), R^(s4) are independently H or CH₃,wherein R^(2a) is H, an alkyl group, an aryl group, a benzyl group, atrityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); R⁵ is H orOR^(2b), wherein R^(2b) is H, an alkyl group, an aryl group, a benzylgroup, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); andR¹⁰ is H; to a second compound with the formula

comprising the step of reacting the first compound under conditionssuitable to effect macrolactonization.
 6. The process of claim 5 forconversion of a compound with the following stereostructure or itsenantiomer

wherein R¹ is H, an alkyl group, an alkenyl group, an alkynyl group, ora halogen atom; R² is H, an alkyl group, a benzyl group, a trityl group,—SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); R^(2d) is H R^(a), R^(b) andR^(c) are independently an alkyl group or an aryl group; R^(d) is analkyl group, an aryl group, an alkoxylalkyl group,—R^(i)SiR^(a)R^(b)R^(c) or a benzyl group, wherein R^(i) is an alkylenegroup; R^(c) is an alkyl group, an allyl group, a benzyl group, an arylgroup, an alkoxy group, or —NR^(g)R^(h) wherein R^(g) and R^(h) areindependently H, an alkyl group or an aryl group; R³ is (CH₂)_(n) wheren is and integer in the range of 0 to 5, —CH₂CH(CH₃)—, —CH═CH—,—CH═C(CH₃)—, or —C≡C—; R⁴ is (CH₂)_(p) where p is an integer in therange of 4 to 12,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH(R^(s2))C(R^(s3))═C(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))CH(R^(s3))CH(R^(s4))—,—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)CH(R^(s1))CH(R^(s2))CH(R^(s3))CH(R^(s4))—,wherein y1 and y2 are 1 and y3, y4 and y5 are independently 0 or 1,R^(k1), R^(k2), R^(k3), R^(k4) and R^(k5) are independently H, —CH₃, orOR^(2a), and R^(s1), R^(s2), R^(s3), R^(s4) are independently H or CH₃,wherein R^(2a) is H, an alkyl group, an aryl group, a benzyl group, atrityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); and R⁵ is H orOR^(2b), wherein R^(2b) is H, an alkyl group, an aryl group, a benzylgroup, a trityl group, —SiR^(a)R^(b)R^(c), CH₂OR^(d), or COR^(e); andR¹⁰ is H to a second compound with the formula


7. The process of claim 6 wherein R¹ is alkenyl; R³ is CH₂CH(CH₃) orCH═C(CH₃); and R⁴ is—(CHR^(k1))_(y1)(CHR^(k2))_(y2)(CHR^(k3))_(y3)(CHR^(k4))_(y4)(CHR^(k5))_(y5)C(R^(s1))═C(R^(s2))C(R^(s3))═C(R^(s4))—wherein y1–y4 are 1, y5 is 0, R^(k1) and R^(k3) are R^(2a), R^(k2) is H,R^(k4) is CH₃, R^(s1)–R^(s4) are H, and R⁵ is OR^(2b).
 8. The process ofclaim 6 wherein R¹ is CH═CH₂ and R⁴ is


9. The process of claim 5 wherein the first compound is reacted with2,4,6-trichlorobenzoylchloride.
 10. The process of claim 6 wherein thefirst compound is reacted with 2,4,6-trichlorobenzoylchloride.